Computational Analysis on the Allostery of Tryptophan Synthase: Relationship between α/β-Ligand Binding and Distal Domain Closure

This article references 70 other publications.

1. 1

   Consalvi, S.; Scarpecci, C.; Biava, M.; Poce, G. Mycobacterial tryptophan biosynthesis: A promising target for tuberculosis drug development?. Bioorg. Med. Chem. Lett. 2019, 29, 126731,  DOI: 10.1016/j.bmcl.2019.126731

   1

   Mycobacterial tryptophan biosynthesis: a promising target for tuberculosis drug development?

   Consalvi, Sara; Scarpecci, Cristina; Biava, Mariangela; Poce, Giovanna

   Bioorganic & Medicinal Chemistry Letters (2019), 29 (23), 126731CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

   A review. The biosynthetic pathways of amino acids are attractive targets for drug development against pathogens with an intracellular behavior like M. tuberculosis (Mtb). Indeed, while in the macrophages Mtb has restricted access to amino acids such as tryptophan (Trp). Auxotrophic Mtb strains, with mutations in the Trp biosynthetic pathway, showed reduced intracellular survival in cultured human and murine macrophages and failed to cause the disease in immunocompetent and immunocompromised mice. Herein we present recent efforts in the discovery of Trp biosynthesis inhibitors.

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2. 2

   Lott, J. S. The tryptophan biosynthetic pathway is essential for Mycobacterium tuberculosis to cause disease. Biochem. Soc. Trans. 2020, 48, 2029– 2037,  DOI: 10.1042/BST20200194

   2

   The tryptophan biosynthetic pathway is essential for Mycobacterium tuberculosis to cause disease

   Lott, J. Shaun

   Biochemical Society Transactions (2020), 48 (5), 2029-2037CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)

   Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is the most significant cause of death from a single infectious agent worldwide. Antibiotic-resistant strains of M. tuberculosis represent a threat to effective treatment, and the long duration, toxicity and complexity of current chemotherapy for antibiotic-resistant disease presents a need for new therapeutic approaches with novel modes of action. M. tuberculosis is an intracellular pathogen that must survive phagocytosis by macrophages, dendritic cells or neutrophils to establish an infection. The tryptophan biosynthetic pathway is required for bacterial survival in the phagosome, presenting a target for new classes of antitubercular compd. The enzymes responsible for the six catalytic steps that produce tryptophan from chorismate have all been characterised in M. tuberculosis, and inhibitors have been described for some of the steps. The innate immune system depletes cellular tryptophan in response to infection in order to inhibit microbial growth, and this effect is likely to be important for the efficacy of tryptophan biosynthesis inhibitors as new antibiotics. Allosteric inhibitors of both the first and final enzymes in the pathway have proven effective, including by a metabolite produced by the gut biota, raising the intriguing possibility that the modulation of tryptophan biosynthesis may be a natural inter-bacterial competition strategy.

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3. 3

   Global tuberculosis report 2021; World Health Organization, 2021.

   There is no corresponding record for this reference.
4. 4

   Dunn, M. F. Allosteric regulation of substrate channeling and catalysis in the tryptophan synthase bienzyme complex. Arch. Biochem. Biophys. 2012, 519, 154– 166,  DOI: 10.1016/j.abb.2012.01.016

   4

   Allosteric regulation of substrate channeling and catalysis in the tryptophan synthase bienzyme complex

   Dunn, Michael F.

   Archives of Biochemistry and Biophysics (2012), 519 (2), 154-166CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

   A review. The tryptophan synthase α2β2 bi-enzyme complex catalyzes the last two steps in the synthesis of L-tryptophan (L-Trp). The α-subunit catalyzes cleavage of 3-indole-D-glycerol 3'-phosphate (IGP) to give indole and D-glyceraldehyde 3'-phosphate (G3P). Indole is then transferred (channeled) via an interconnecting 25 Å-long tunnel, from the α-subunit to the β-subunit where it reacts with L-Ser in a pyridoxal 5'-phosphate-dependent reaction to give L-Trp and a water mol. The efficient utilization of IGP and L-Ser by tryptophan synthase to synthesize L-Trp utilizes a system of allosteric interactions that (1) function to switch the α-site on and off at different stages of the β-subunit catalytic cycle, and (2) prevent the escape of the channeled intermediate, indole, from the confines of the α- and β-catalytic sites and the interconnecting tunnel. This review discusses in detail the chem. origins of the allosteric interactions responsible both for switching the α-site on and off, and for triggering the conformational changes between open and closed states which prevent the escape of indole from the bienzyme complex.

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5. 5

   Barends, T. R. M.; Dunn, M. F.; Schlichting, I. Tryptophan synthase, an allosteric molecular factory. Curr. Opin. Chem. Biol. 2008, 12, 593– 600,  DOI: 10.1016/j.cbpa.2008.07.011

   5

   Tryptophan synthase, an allosteric molecular factory

   Barends, Thomas R. M.; Dunn, Michael F.; Schlichting, Ilme

   Current Opinion in Chemical Biology (2008), 12 (5), 593-600CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)

   A review. Tryptophan synthase (TrpS) is a pyridoxal phosphate-contg. bifunctional enzyme that catalyzes the last two steps in the biosynthesis of L-tryptophan. Indole, an intermediate generated at the active site of the α-subunit is channeled via a 25 Å long tunnel to the β-active site where it reacts with an aminoacrylate intermediate derived from L-serine. The two reactions are kept in phase by allosteric interactions between the two subunits. The recent development of novel α-site ligands and α-reaction transition state analogs combined with kinetic and crystal structure anal. of Salmonella typhimurium tryptophan synthase has provided new insights into the allosteric regulation of substrate channeling, the reaction mechanisms of the α and β active sites, and the influence of structural dynamics.

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6. 6

   Wellington, S.; Nag, P. P.; Michalska, K.; Johnston, S. E.; Jedrzejczak, R. P.; Kaushik, V. K.; Clatworthy, A. E.; Siddiqi, N.; McCarren, P.; Bajrami, B. A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. Nat. Chem. Biol. 2017, 13, 943– 950,  DOI: 10.1038/nchembio.2420

   6

   A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase

   Wellington, Samantha; Nag, Partha P.; Michalska, Karolina; Johnston, Stephen E.; Jedrzejczak, Robert P.; Kaushik, Virendar K.; Clatworthy, Anne E.; Siddiqi, Noman; McCarren, Patrick; Bajrami, Besnik; Maltseva, Natalia I.; Combs, Senya; Fisher, Stewart L.; Joachimiak, Andrzej; Schreiber, Stuart L.; Hung, Deborah T.

   Nature Chemical Biology (2017), 13 (9), 943-950CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)

   New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromol. synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine deriv., BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB α-β-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.

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7. 7

   Michalska, K.; Chang, C.; Maltseva, N. I.; Jedrzejczak, R.; Robertson, G. T.; Gusovsky, F.; McCarren, P.; Schreiber, S. L.; Nag, P. P.; Joachimiak, A. Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase. Protein Sci. 2020, 29, 779– 788,  DOI: 10.1002/pro.3825

   7

   Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase

   Michalska, Karolina; Chang, Changsoo; Maltseva, Natalia I.; Jedrzejczak, Robert; Robertson, Gregory T.; Gusovsky, Fabian; McCarren, Patrick; Schreiber, Stuart L.; Nag, Partha P.; Joachimiak, Andrzej

   Protein Science (2020), 29 (3), 779-788CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)

   Global dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel mol. targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. Here we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chem. scaffolds. We compare our results with previously reported structural and biochem. studies of another, azetidine-contg. M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes.

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8. 8

   Yutani, K.; Ogasahara, K.; Tsujita, T.; Kanemoto, K.; Matsumoto, M.; Tanaka, S.; Miyashita, T.; Matsushiro, A.; Sugino, Y.; Miles, E. W. Tryptophan synthase alpha subunit glutamic acid 49 is essential for activity. Studies with 19 mutants at position 49. J. Biol. Chem. 1987, 262, 13429– 13433,  DOI: 10.1016/S0021-9258(19)76444-8

   8

   Tryptophan synthase α subunit glutamic acid 49 is essential for activity. Studies with 19 mutants at position 49

   Yutani, Katsuhide; Ogasahara, Kyoko; Tsujita, Tadahiro; Kanemoto, Kohji; Matsumoto, Midori; Tanaka, Shigeo; Miyashita, Tomoyuki; Matsushiro, Aizo; Sugino, Yoshinobu; Miles, Edith Wilson

   Journal of Biological Chemistry (1987), 262 (28), 13429-33CODEN: JBCHA3; ISSN:0021-9258.

   A complete set of 20 variants of tryptophan synthase (I) α subunit of E. coli at position 49 was obtained to extend previous studies on the effects of single amino acid replacements at position 49 on structure and function. Thirteen mutant α subunits were newly constructed by site-directed mutagenesis using oligonucleotides. Six mutants were available from previous studies. The wild-type and all of the mutant α subunits formed α2β2 complexes with I β2 subunit with similar assocn. const. and similarly stimulate the activity of the β2 subunit in the synthesis of L-tryptophan from L-serine and indole. Thus, none of the changes at position 49 produceds a change in the conformation of the α subunit which significantly interfered with normal subunit interaction. However, the 19 mutant α2β2 complexes were completely devoid of activity in reactions normally catalyzed by the active site of the α subunit. This is the 1st time that these several activities were measured with a series of highly purified α subunits altered by mutation at a single site. The finding the the mutant in which glutamic acid-49 substituted with aspartic acid was totally devoid of α subunit activity was esp. significant and was strong evidence that glutamic acid- 49 is an essential catalytic base in the reaction catalyzed by the α subunit. This result was consistent with the results of previous genetic studies, with evolutionary comparisons using sequence anal., and with recent results from x-ray crystallog. of the α2β2 complex of I from Salmonella typhimurium.

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9. 9

   Hyde, C. C.; Ahmed, S. A.; Padlan, E. A.; Miles, E. W.; Davies, D. R. Three-dimensional structure of the tryptophan synthase alpha 2 beta 2 multienzyme complex from Salmonella typhimurium. J. Biol. Chem. 1988, 263, 17857– 17871,  DOI: 10.1016/S0021-9258(19)77913-7

   9

   Three-dimensional structure of the tryptophan synthase α2β2 multienzyme complex from Salmonella typhimurium

   Hyde, C. Craig; Ahmed, S. Ashrafudin; Padlan, Eduardo A.; Miles, Edith W.; Davies, David R.

   Journal of Biological Chemistry (1988), 263 (33), 17857-71CODEN: JBCHA3; ISSN:0021-9258.

   The 3-dimensional structure of the α2β2 complex of tryptophan synthase from S. typhimurium was detd. by x-ray crystallog. at 2.5 Å resoln. The 4 polypeptide chains are arranged nearly linearly in an αββα order forming a complex 150 Å long. The overall polypeptide fold of the smaller α subunit, which cleaves indole glycerol phosphate, is that of an 8-fold α/β barrel. The α subunit active site was located by difference Fourier anal. of the binding of indole propanol phosphate, a competitive inhibitor of the α subunit and a close structural analog of the natural substrate. The larger pyridoxal phosphate-depending β subunit contains 2 domains of nearly equal size, folded into similar helix/sheet/helix structures. The binding site for the coenzyme pyridoxal phosphate lies deep within the interface between the 2 β subunit domains. The active sites of neighboring α and β subunits are sepd. by a distance of ∼25 Å. A tunnel with a diam. match that of the intermediate substrate indole connects these active sites. The tunnel is believed to facilitate the diffusion of indole from its point of prodn. in the α subunit active site to the site of tryptophan synthesis in the β active site and thereby prevent its escape to the solvent during catalysis.

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10. 10

    Dunn, M. F.; Aguilar, V.; Brzović, P.; Drewe, W. F.; Houben, K. F.; Leja, C. A.; Roy, M. The tryptophan synthase bienzyme complex transfers indole between the α and β sites via a 25-30 Å long tunnel. Biochemistry 1990, 29, 8598– 8607,  DOI: 10.1021/bi00489a015

    10

    The tryptophan synthase bienzyme complex transfers indole between the α- and β-sites via a 25-30 Å long tunnel

    Dunn, Michael F.; Aguilar, Valentin; Brzovic, Peter; Drewe, William F., Jr.; Houben, Karl F.; Leja, Catherine A.; Roy, Melinda

    Biochemistry (1990), 29 (37), 8598-607CODEN: BICHAW; ISSN:0006-2960.

    The bacterial tryptophan synthase bioenzyme complexes (with subunit compn. α2β2) catalyze the last 2 steps in the biosynthesis of L-tryptophan. For L-tryptophan synthesis, indole, the common metabolite, must be transferred by some mechanism from the α-catalytic site to the β-catalytic site. The x-ray structure of Salmonella typhimurium tryptophan synthase shows the catalytic sites of each α-β subunit pair are connected by a 25-30 Å long tunnel. Since the S. typhimurium and Escherichia coli enzymes have nearly identical sequences, the E. coli enzyme must have a similar tunnel. Here, rapid kinetic studies in combination with chem. probes that signal the bond formation step between indole (or nucleophilic indole analogs) and the α-aminoacrylate Schiff base intermediate, E(A-A), bound to the β-site are used to investigate tunnel function in the E. coli enzyme. If the tunnel is the phys. conduit for transfer of indole from the α-site to the β-site, then ligands that block the tunnel should also inhibit the rate at which indole and indole analogs from external soln. react with E(A-A). When DL-α-glycerol 3-phosphate (GP) is bound to the α-site, the rate of reaction of indole and nucleophilic indole analogs with E(A-A) is strongly inhibited. These compds. appear to gain access to the β-site via the α-site and the tunnel, and this access is blocked by the binding of GP to the α-site. However, when small nucleophiles such as hydroxylamine, hydrazine, or N-methylhydroxylamine are substituted for indole, the rate of quinonoid formation is only slightly affected by the binding of GP. Furthermore, the reactions of L-serine and L-tryptophan with α2β2 show only small rate effects due to the binding of GP. From these expts., the following conclusions can be drawn: (1) L-serine and L-tryptophan gain access to the β-site of α2β2 directly from soln. (2) The small effects of GP on the rates of the L-serine and L-tryptophan reactions are due to GP-mediated allosteric interactions between the α- and β-sites. (3) The α-site and the interconnecting tunnel function as a highly preferred route for the transfer of indole and indole analogs such as benzimidazole, indoline, or aniline between soln. and the β-catalytic site of E(A-A). (4) GP inhibits the access of these mols. to the β-site by blocking the tunnel opening at the α-site. (5) The entry of small nucleophiles into the β-site of E(A-A) from soln. is not blocked by GP. (6) Either GP does not completely block the tunnel opening, or these small nucleophiles have an alternative route of access (perhaps through a leak in the tunnel wall or directly through the β-site).

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11. 11

    Casino, P.; Niks, D.; Ngo, H.; Pan, P.; Brzovic, P.; Blumenstein, L.; Barends, T. R.; Schlichting, I.; Dunn, M. F. Allosteric regulation of tryptophan synthase channeling: The internal aldimine probed by trans-3-indole-3′-acrylate binding. Biochemistry 2007, 46, 7728– 7739,  DOI: 10.1021/bi700386b

    11

    Allosteric Regulation of Tryptophan Synthase Channeling: The Internal Aldimine Probed by trans-3-Indole-3'-acrylate Binding

    Casino, Patricia; Niks, Dimitri; Ngo, Huu; Pan, Peng; Brzovic, Peter; Blumenstein, Lars; Barends, Thomas Reinier; Schlichting, Ilme; Dunn, Michael F.

    Biochemistry (2007), 46 (26), 7728-7739CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Substrate channeling in the tryptophan synthase bienzyme complex from Salmonella typhimurium is regulated by allosteric interactions triggered by binding of ligand to the α-site and covalent reaction at the β-site. These interactions switch the enzyme between low-activity forms with open conformations and high-activity forms with closed conformations. Previously, allosteric interactions have been demonstrated between the α-site and the external aldimine, α-aminoacrylate, and quinonoid forms of the β-site. Here we employ the chromophoric L-Trp analog, trans-3-indole-3'-acrylate (IA), and noncleavable α-site ligands (ASLs) to probe the allosteric properties of the internal aldimine, E(Ain). The ASLs studied are α-D,L-glycerol phosphate (GP) and D-glyceraldehyde 3-phosphate (G3P), and examples of two new classes of high-affinity α-site ligands, N-(4'-trifluoromethoxybenzoyl)-2-aminoethyl phosphate (F6) and N-(4'-trifluoromethoxybenzenesulfonyl)-2-aminoethyl phosphate (F9), that were previously shown to bind to the α-site by optical spectroscopy and x-ray crystal structures. The binding of IA to the β-site is stimulated by the binding of GP, G3P, F6, or F9 to the α-site. The binding of ASLs was found to increase the affinity of the β-site of E(Ain) for IA by 4-5-fold, demonstrating for the first time that the β-subunit of the E(Ain) species undergoes a switching between low- and high-affinity states in response to the binding of ASLs.

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12. 12

    Brzović, P. S.; Ngo, K.; Dunn, M. F. Allosteric interactions coordinate catalytic activity between successive metabolic enzymes in the tryptophan synthase bienzyme complex. Biochemistry 1992, 31, 3831– 3839,  DOI: 10.1021/bi00130a014

    12

    Allosteric interactions coordinate catalytic activity between successive metabolic enzymes in the tryptophan synthase bienzyme complex

    Brzovic, Peter S.; Ngo Khiet; Dunn, Michael F.

    Biochemistry (1992), 31 (15), 3831-9CODEN: BICHAW; ISSN:0006-2960.

    Tryptophan synthase from enteric bacteria is an α2β2 bienzyme complex that catalyzes the final 2 reactions in the biosynthesis of L-tryptophan (L-Trp) from 3-indole-D-glycerol 3'-phosphate (IGP) and L-serine (L-Ser). The bienzyme complex exhibits reciprocal ligand-mediated allosteric interactions between the heterologous subunits, but the relation between allostery and catalysis has not been completely defined. Here, rapid-scanning stopped-flow (RSSF) UV-visible spectroscopy was utilized to study the relation between allostery and catalysis in the αβ-reaction catalyzed by the bienzyme complex from Salmonella typhimurium. The pre-steady-state spectral changes that occur when L-Ser and IGP are mixed simultaneously with the α32β2 complex showed that IGP binding to the α-site accelerates the formation of α-aminoacylate [E(A-A)] from L-Ser at the β-site. Through the use of L-Ser analogs, it is shown that the formation of the E(A-A) intermediate is the chem. signal which triggers the conformational transition that activates the α-subunit. β-Subunit ligands, such as L-Trp, that react to form covalent intermediates at the β-site, but are incapable of E(A-A) formation, did not stimulate the activity of the α-subunit. Titrn. expts. showed that the affinity of D-glyceraldehyde 3-phosphate and α-glycerol phosphate at the α-site was dependent upon the nature of the chem. intermediate present at the β-active site. These results showed that ligand-dependent allosteric interactions between heterologous subunits in the bienzyme complex serve to coordinate catalytic events at the α- and β-active sites to ensure the efficient synthesis of L-Trp. It is proposed that these ligand-dependent allosteric phenomena are accompanied by conformational transitions in both the α- and β-subunits between open and closed conformations that control ligand affinity and catalytic activity.

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13. 13

    Ngo, H.; Kimmich, N.; Harris, R.; Niks, D.; Blumenstein, L.; Kulik, V.; Barends, T. R.; Schlichting, I.; Dunn, M. F. Allosteric Regulation of Substrate Channeling in Tryptophan Synthase: Modulation of the l-Serine Reaction in Stage I of the β-Reaction by α-Site Ligands. Biochemistry 2007, 46, 7740– 7753,  DOI: 10.1021/bi7003872

    13

    Allosteric Regulation of Substrate Channeling in Tryptophan Synthase: Modulation of the L-Serine Reaction in Stage I of the β-Reaction by α-Site Ligands

    Ngo, Huu; Kimmich, Novelle; Harris, Rodney; Niks, Dimitri; Blumenstein, Lars; Kulik, Victor; Barends, Thomas Reinier; Schlichting, Ilme; Dunn, Michael F.

    Biochemistry (2007), 46 (26), 7740-7753CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    In the tryptophan synthase bienzyme complex, indole produced by substrate cleavage at the α-site is channeled to the β-site via a 25 Å long tunnel. Within the β-site, indole and L-Ser react with pyridoxal 5'-phosphate in a two-stage reaction to give L-Trp. In stage I, L-Ser forms an external aldimine, E(Aex1), which converts to the α-aminoacrylate aldimine, E(A-A). Formation of E(A-A) at the β-site activates the α-site >30-fold. In stage II, indole reacts with E(A-A) to give L-Trp. The binding of α-site ligands (ASLs) exerts strong allosteric effects on the reaction of substrates at the β-site: the distribution of intermediates formed in stage I is shifted in favor of E(A-A), and the binding of ASLs triggers a conformational change in the β-site to a state with an increased affinity for L-Ser. Here, we compare the behavior of new ASLs as allosteric effectors of stage I with the behavior of the natural product, D-glyceraldehyde 3-phosphate. Rapid kinetics and kinetic isotope effects show these ASLs bind with affinities ranging from micro- to millimolar, and the rate-detg. step for conversion of E(Aex1) to E(A-A) is increased by 8-10-fold. To derive a structure-based mechanism for stage I, x-ray structures of both the E(Aex1) and E(A-A) states complexed with the different ASLs were detd. and compared with structures of the ASL complexes with the internal aldimine.

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14. 14

    Brzović, P. S.; Sawa, Y.; Hyde, C. C.; Miles, E. W.; Dunn, M. F. Evidence that mutations in a loop region of the α-subunit inhibit the transition from an open to a closed conformation in the tryptophan synthase bienzyme complex. J. Biol. Chem. 1992, 267, 13028– 13038,  DOI: 10.1016/S0021-9258(18)42377-0

    14

    Evidence that mutations in a loop region of the α-subunit inhibit the transition from an open to a closed conformation in the tryptophan synthase bienzyme complex

    Brzovic, Peter S.; Sawa, Yoshihiro; Hyde, C. Craig; Miles, Edith W.; Dunn, Michael F.

    Journal of Biological Chemistry (1992), 267 (18), 13028-38CODEN: JBCHA3; ISSN:0021-9258.

    Rapid-scanning stopped-flow (RSSF) UV-visible spectroscopy has been used to investigate the effects of single amino acid mutations in the α-subunit of the Salmonella typhimurium tryptophan synthase bienzyme complex on the reactivity at the β-subunit active site located 25-30 Å distant. The pyridoxal 5'-phosphate (PLP) cofactor provides a convenient spectroscopic probe to directly monitor catalytic events at the β-active site. Single substitutions of Phe for Glu at position 49, Leu for Gly at position 51, or Tyr for Asp at position 60 in the α-subunit strongly alter the obsd. steady state and pre-steady state inhibitory effects of the α-subunit-specific ligand α-glycerophosphate (GP) on the PLP-dependent β-reaction. However, similar GP-induced allosteric effects on the distribution of covalent intermediates bound at the β-site that are obsd. with the wild-type enzyme (Houben, K. F.; Dunn, M. F., 1990) also are obsd. for each of the mutant bienzyme complexes. These results support the hypothesis that the preferred pathway of indole from soln. into the β-site is via the α-site and the interconnecting tunnel (Dunn, M. F. et al., 1990). Residues αE49, αG51, and αD60 are part of a highly conserved inserted sequence in the α/β-barrel topol. of the α-subunit. The GP-induced inhibition of the β-reaction is proposed to result, in part, from a ligand-dependent conformational change from an open to a closed structure of the α-subunit which involves this region of the α-subunit and serves to obstruct the direct access of indole into the tunnel. These findings suggest that the altered kinetic behavior obsd. for the α-mutants in the presence of GP reflects an impaired ability of the modified bienzyme complex to undergo the conformational transition from the open to the closed form.

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15. 15

    Brzović, P. S.; Kayastha, A. M.; Miles, E. W.; Dunn, M. F. Substitution of glutamic acid 109 by aspartic acid alters the substrate specificity and catalytic activity of the β-subunit in the tryptophan synthase bienzyme complex from Salmonella typhimurium. Biochemistry 1992, 31, 1180– 1190,  DOI: 10.1021/bi00119a030

    15

    Substitution of glutamic acid 109 by aspartic acid alters the substrate specificity and catalytic activity of the β-subunit in the tryptophan synthase bienzyme complex from Salmonella typhimurium

    Brzovic, Peter S.; Kayastha, Arvind M.; Miles, Edith Wilson; Dunn, Michael F.

    Biochemistry (1992), 31 (4), 1180-90CODEN: BICHAW; ISSN:0006-2960.

    In an effort to understand the catalytic mechanism of the tryptophan synthase β-subunit from S. typhimurium, possible functional active site residues were identified (on the basis of the 3-dimensional crystal structure of the bienzyme complex) and targeted for anal. utilizing site-directed mutagenesis. The chromophoric properties of the pyridoxal 5'-phosphate cofactor provided a particularly convenient and sensitive spectral probe to directly investigate changes in catalytic events which occur upon modification of the β-subunit. Substitution of Asp for Glu-109 in the β-subunit altered both the catalytic activity and the substrate specificity of the β-reaction. Steady-state data revealed that the β-reaction catalyzed by the βE109D α2β2 mutant enzyme complex was reduced 27-fold compared to the wild-type enzyme. Rapid-scanning stopped-flow (RSSF) UV-visible spectroscopy showed that the mutation did not seriously affect the pre-steady-state reaction of the βE109D mutant with L-serine to form the α-aminoacrylate intermediate, E(A-A). Binding of the α-subunit-specific ligand, α-glycerol phosphate (GP) to the α2β2 complex exerted the same allosteric effects on the β-subunit as obsd. with the wild-type enzyme. However, the pre-steady-state spectral changes for the reaction of indole with E(A-A) showed that the formation of the L-tryptophan quinonoid, E(Q3), was drastically altered. Discrimination against E(Q3) formation was also obsd. for the binding of L-tryptophan to the mutant α2β2 complex in the reverse reaction. In contrast, substitution of Asp for Glu-109 increased the apparent affinity of the βE109D α-aminoacrylate complex for the indole analog, indoline, and resulted in the increased rate of synthesis of the amino acid product, dihydroiso-L-tryptophan. Thus, the mutation affects the covalent bond-forming addn. reactions and the nucleophile specificity of the β-reaction catalyzed by the bienzyme complex.

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16. 16

    Brzović, P. S.; Hyde, C. C.; Miles, E. W.; Dunn, M. F. Characterization of the functional role of a flexible loop in the α-subunit of tryptophan synthase from Salmonella typhimurium by rapid-scanning, stopped-flow spectroscopy and site-directed mutagenesis. Biochemistry 1993, 32, 10404– 10413,  DOI: 10.1021/bi00090a016

    16

    Characterization of the functional role of a flexible loop in the α-subunit of tryptophan synthase from Salmonella typhimurium by rapid-scanning, stopped-flow spectroscopy and site-directed mutagenesis

    Brzovic, Peter S.; Hyde, C. Craig; Miles, Edith W.; Dunn, Michael F.

    Biochemistry (1993), 32 (39), 10404-13CODEN: BICHAW; ISSN:0006-2960.

    The function of a flexible loop (loop 6) in the α subunit from the tryptophan synthase α2β2 bienzyme complex was investigated utilizing rapid-scanning (RSSF) and single-wavelength (SWSF) stopped-flow spectroscopies. Loop 6 is an extended sequence of residues which connects β-strand 6 with α-helix 6 in the β/α-barrel fold of the α subunit. Substitution of Leu for Arg-179 near the base of loop 6 did not significantly affect either the assocn. of the α and β subunits to form the bienzyme complex or the kinetics of the reaction of indole with L-Ser to form L-Trp, the process catalyzed by the wild-type β subunit. However, the α subunit-specific ligand, glycerol phosphate (GP), which is an inhibitor of the wild-type β reaction, was a much less effective inhibitor of the αR179L-catalyzed β subunit reaction. Equil. titrn. studies showed that the affinity of GP for the α-site when either L-Ser or Gly was bound at the β-site was reduced by nearly 100- and 200-fold, resp. SWSF anal. of the reaction. of 3-indole-D-glycerol 3'-phosphate (IGP) and L-Ser to form L-Trp catalyzed by the bienzyme complex revealed a 15-fold redn. in the binding affinity of the α site substrate, IGP, in the reaction catalyzed by the αR179L mutant as compared to the wild-type enzyme. These studies showed that loop 6 is important both for ligand binding to the α site and for the ligand-induced conformational transition of the α subunit from an open to a closed structure. Modeling studies, based on extensive structural homol. of the α subunit with the glycolytic enzyme, triosephosphate isomerase (TIM), predicted that closure of loop 6 induced by ligand binding at the α active site would effectively sequester the bound substrate from the solvent and trap indole, produced from the cleavage of IGP, within the confines of the bienzyme complex. This conformational transition would promote the diffusion of indole to the β active site via the interconnecting tunnel and would help ensure the close coordination of α and β subunit catalytic activities.

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17. 17

    Schneider, T. R.; Gerhardt, E.; Lee, M.; Liang, P.-H.; Anderson, K. S.; Schlichting, I. Loop Closure and Intersubunit Communication in Tryptophan Synthase. Biochemistry 1998, 37, 5394– 5406,  DOI: 10.1021/bi9728957

    17

    Loop closure and intersubunit communication in tryptophan synthase

    Schneider, Thomas R.; Gerhardt, Eva; Lee, Minsu; Liang, Po-Huang; Anderson, Karen S.; Schlichting, Ilme

    Biochemistry (1998), 37 (16), 5394-5406CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Crystal structures of wild-type tryptophan synthase α2β2 complexes from Salmonella typhimurium were detd. to investigate the mechanism of allosteric activation of the α-subunit reaction by the aminoacrylate intermediate formed at the β-subunit active site. Using a flow cell, the aminoacrylate (A-A) intermediate of the β-subunit reaction (TRPSA-AF-IPP) was generated in the crystal under steady state conditions in the presence of serine and the α-subunit site inhibitor, 5-fluoroindole propanol phosphate (F-IPP). A model for the conformation of the Schiff base between the aminoacrylate and the β-subunit cofactor, pyridoxal phosphate (PLP), is presented. The TRPSA-AF-IPP structure was compared with structures of the enzyme detd. in the absence (TRPS) and presence (TRPSF-IPP) of F-IPP. A detailed model for binding of F-IPP to the α-subunit is presented. In contrast to previous reports, the authors found that the presence of an α-site alone ligand is sufficient for loop αL6 closure atop the α-subunit active site. Part of this loop, αThr-183, is important not only for positioning the catalytic αAsp-60 but also for coordinating the concomitant ordering of loop αL2 upon F-IPP binding. On the basis of the 3 structures, a pathway for communication between the α- and β-subunit active sites was established. The central element of this pathway is a newly defined rigid, but movable, domain that on one side interacts with the α-subunit via loop αL2 and on the other side with the β-subunit active site. These findings provide a structural basis for understanding the allosteric properties of tryptophan synthase.

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18. 18

    Jhee, K.-H.; Yang, L.-H.; Ahmed, S. A.; McPhie, P.; Rowlett, R.; Miles, E. W. Mutation of an Active Site Residue of Tryptophan Synthase (β-Serine 377) Alters Cofactor Chemistry. J. Biol. Chem. 1998, 273, 11417– 11422,  DOI: 10.1074/jbc.273.19.11417

    18

    Mutation of an active site residue of tryptophan synthase (β-serine 377) alters cofactor chemistry

    Jhee, Kwang-Hwan; Yang, Li-hong; Ahmed, S. Ashraf; McPhie, Peter; Rowlett, Roger; Wilson Miles, Edith

    Journal of Biological Chemistry (1998), 273 (19), 11417-11422CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    To better understand how an enzyme controls cofactor chem., we have changed a tryptophan synthase residue that interacts with the pyridine nitrogen of the pyridoxal phosphate cofactor from a neutral Ser (β-Ser377) to a neg. charged Asp or Glu. The spectroscopic properties of the mutant enzymes are altered and become similar to those of tryptophanase and aspartate aminotransferase, enzymes in which an Asp residue interacts with the pyridine nitrogen of pyridoxal phosphate. The absorption spectrum of each mutant enzyme undergoes a pH-dependent change (pKa ∼ 7.7) from a form with a protonated internal aldimine nitrogen (λmax = 416 nm) to a deprotonated form (λmax = 336 nm), whereas the absorption spectra of the wild type tryptophan synthase β2 subunit and α2β2 complex are pH-independent. The reaction of the S377D α2β2 complex with L-serine, L-tryptophan, and other substrates results in the accumulation of pronounced absorption bands (λmax = 498-510 nm) ascribed to quinonoid intermediates. We propose that the engineered Asp or Glu residue changes the cofactor chem. by stabilizing the protonated pyridine nitrogen of pyridoxal phosphate, reducing the pKa of the internal aldimine nitrogen and promoting formation of quinonoid intermediates.

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19. 19

    Ferrari, D.; Yang, L.-H.; Miles, E. W.; Dunn, M. F. βD305A Mutant of Tryptophan Synthase Shows Strongly Perturbed Allosteric Regulation and Substrate Specificity. Biochemistry 2001, 40, 7421– 7432,  DOI: 10.1021/bi002892l

    19

    βD305A Mutant of Tryptophan Synthase Shows Strongly Perturbed Allosteric Regulation and Substrate Specificity

    Ferrari, Davide; Yang, Li-Hong; Miles, Edith W.; Dunn, Michael F.

    Biochemistry (2001), 40 (25), 7421-7432CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Substrate channeling in the tryptophan synthase bienzyme is regulated by allosteric interactions. Allosteric signals are transmitted via a scaffolding of structural elements that includes a monovalent cation-binding site and salt-bridging interactions between the side chains of βAsp 305, βArg 141, βLys 167, and αAsp 56 that appear to modulate the interconversion between open and closed conformations. βAsp 305 also interacts with the hydroxyl group of the substrate L-Ser in some structures. One possible functional role for βAsp 305 is to ensure the allosteric transmission that triggers the switching of αβ-dimeric units between open and closed conformations of low and high activity. This work shows that substitution of βAsp 305 with Ala (βD305A) decreases the affinity of the β-site for the substrate L-Ser, destabilizes the enzyme-bound α-aminoacrylate, E(A-A), and quinonoid species, E(Q), and changes the nucleophile specificity of the β-reaction. The altered specificity provides a biosynthetic route for new L-amino acids derived from substrate analogs. βD305A also shows an increased rate of formation of pyruvate upon reaction with L-Ser relative to the wild-type enzyme. The formation of pyruvate is strongly inhibited by the binding of benzimidazole to E(A-A). Upon reaction with L-Ser and in the presence of the α-site substrate analog, α-glycerol phosphate, the Na+ form of βD305A undergoes inactivation via reaction of nascent α-aminoacrylate with bound PLP. This work establishes important roles for βAsp 305 both in the conformational change between open and closed states that takes place at the β-site during the formation of the E(A-A) and in substrate binding and recognition.

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20. 20

    Kulik, V.; Weyand, M.; Seidel, R.; Niks, D.; Arac, D.; Dunn, M. F.; Schlichting, I. On the Role of αThr183 in the Allosteric Regulation and Catalytic Mechanism of Tryptophan Synthase. J. Mol. Biol. 2002, 324, 677– 690,  DOI: 10.1016/S0022-2836(02)01109-9

    20

    On the Role of αThr183 in the Allosteric Regulation and Catalytic Mechanism of Tryptophan Synthase

    Kulik, Victor; Weyand, Michael; Seidel, Ralf; Niks, Dimitri; Arac, Demet; Dunn, Michael F.; Schlichting, Ilme

    Journal of Molecular Biology (2002), 324 (4), 677-690CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Science Ltd.)

    The catalytic activity and substrate channeling of the pyridoxal 5'-phosphate-dependent tryptophan synthase α2β2 complex is regulated by allosteric interactions that modulate the switching of the enzyme between open, low activity and closed, high activity states during the catalytic cycle. The highly conserved αThr183 residue is part of loop αL6 and is located next to the α-active site and forms part of the α-β subunit interface. The role of the interactions of αThr183 in α-site catalysis and allosteric regulation was investigated by analyzing the kinetics and crystal structures of the isosteric mutant αThr183Val. The mutant displays strongly impaired allosteric α-β communication, and the catalytic activity of the α-reaction is reduced one hundred fold, whereas the β-activity is not affected. The structural work establishes that the basis for the missing inter-subunit signaling is the lack of loop αL6 closure even in the presence of the α-subunit ligands, 3-indolyl-D-glycerol 3'-phosphate, or 3-indolylpropanol 3'-phosphate. The structural basis for the reduced α-activity has its origins in the missing hydrogen bond between αThr183 and the catalytic residue, αAsp60.

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21. 21

    Kulik, V.; Hartmann, E.; Weyand, M.; Frey, M.; Gierl, A.; Niks, D.; Dunn, M. F.; Schlichting, I. On the Structural Basis of the Catalytic Mechanism and the Regulation of the Alpha Subunit of Tryptophan Synthase from Salmonella typhimurium and BX1 from Maize, Two Evolutionarily Related Enzymes. J. Mol. Biol. 2005, 352, 608– 620,  DOI: 10.1016/j.jmb.2005.07.014

    21

    On the Structural Basis of the Catalytic Mechanism and the Regulation of the Alpha Subunit of Tryptophan Synthase from Salmonella typhimurium and BX1 from Maize, Two Evolutionarily Related Enzymes

    Kulik, Victor; Hartmann, Elisabeth; Weyand, Michael; Frey, Monika; Gierl, Alfons; Niks, Dimitri; Dunn, Michael F.; Schlichting, Ilme

    Journal of Molecular Biology (2005), 352 (3), 608-620CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)

    Indole is a reaction intermediate in at least two biosynthetic pathways in maize seedlings. In the primary metab., the α-subunit (TSA) of the bifunctional tryptophan synthase (TRPS) catalyzes the cleavage of indole 3-glycerol phosphate (IGP) to indole and D-glyceraldehyde 3-phosphate (G3P). Subsequently, indole diffuses through the connecting tunnel to the β-active site where it is condensed with serine to form tryptophan and water. The maize enzyme, BX1, a homolog of TSA, also cleaves IGP to G3P and indole, and the indole is further converted to 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one, a secondary plant metabolite. BX1 cleaves IGP significantly faster to G3P and indole than does TSA. In line with their different biol. functions, these two evolutionary related enzymes differ significantly in their regulatory aspects while catalyzing the same chem. Here, the mechanism of IGP cleavage by TSA was analyzed using a novel transition state analog generated in situ by reaction of 2-aminophenol and G3P. The crystal structure of the complex shows an Sp3-hybridized atom corresponding to the C3 position of IGP. The catalytic αGlu49 rotates to interact with the Sp3-hybridized atom and the 3' hydroxyl group suggesting that it serves both as proton donor and acceptor in the α-reaction. The second catalytic residue, αAsp60 interacts with the atom corresponding to the indolyl nitrogen, and the catalytically important loop αL6 is in the closed, high activity conformation. Comparison of the TSA and TSA-transition state analog structures with the crystal structure of BX1 suggests that the faster catalytic rate of BX1 may be due to a stabilization of the active conformation: loop αL6 is closed and the catalytic glutamate is in the active conformation. The latter is caused by a substitution of the residues that stabilize the inactive conformation in TRPS.

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22. 22

    Weyand, M.; Schlichting, I. Crystal Structure of Wild-Type Tryptophan Synthase Complexed with the Natural Substrate Indole-3-glycerol Phosphate. Biochemistry 1999, 38, 16469– 16480,  DOI: 10.1021/bi9920533

    22

    Crystal structure of wild-type tryptophan synthase complexed with the natural substrate indole-3-glycerol phosphate

    Weyand, Michael; Schlichting, Ilme

    Biochemistry (1999), 38 (50), 16469-16480CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Freeze trapping was used to stabilize the Michaelis complex of wild-type tryptophan synthase and the α-subunit substrate indole-3-glycerol phosphate (IGP) and detd. its structure to 1.8 Å resoln. In addn., the 1.4 Å resoln. structure of the complex with indole-3-propanol phosphate (IPP), a noncleavable IGP analog was detd. The interaction of the 3'-hydroxyl of IGP with the catalytic αGlu49 leads to a twisting of the propane chain and to a repositioning of the indole ring compared to IPP. Concomitantly, the catalytic αAsp60 rotates, resulting in a translocation of the COMM domain [βGly102-βGly189, for definition see Schneider et al. (1998) Biochem. 37, 5394-5406] in a direction opposite to the one in the IPP complex. This results in loss of the allosteric sodium ion bound at the β-subunit and an opening of the β-active site, thereby making the cofactor pyridoxal 5'-phosphate (PLP) accessible to solvent and thus serine binding. These findings form the structural basis for the information transfer from the α- to the β-subunit and may explain the affinity increase of the β-active site for serine upon IGP binding.

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23. 23

    Nishio, K.; Morimoto, Y.; Ishizuka, M.; Ogasahara, K.; Tsukihara, T.; Yutani, K. Conformational Changes in the α-Subunit Coupled to Binding of the β2-Subunit of Tryptophan Synthase from Escherichia coli: Crystal Structure of the Tryptophan Synthase α-Subunit Alone. Biochemistry 2005, 44, 1184– 1192,  DOI: 10.1021/bi047927m

    23

    Conformational Changes in the α-Subunit Coupled to Binding of the β2-Subunit of Tryptophan Synthase from Escherichia coli: Crystal Structure of the Tryptophan Synthase α-Subunit Alone

    Nishio, Kazuya; Morimoto, Yukio; Ishizuka, Manabu; Ogasahara, Kyoko; Tsukihara, Tomitake; Yutani, Katsuhide

    Biochemistry (2005), 44 (4), 1184-1192CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    When the tryptophan synthase α- and β2-subunits combine to form the α2β2-complex, the enzymic activity of each subunit is stimulated by 1-2 orders of magnitude. To elucidate the structural basis of this mutual activation, it is necessary to det. the structures of the α- and β-subunits alone and together with the α2β2-complex. The crystal structures of the tryptophan synthase α2β2-complex from Salmonella typhimurium (Stα2β2-complex) have already been reported. However, the structures of the subunit alone from mesophiles have not yet been detd. The structure of the tryptophan synthase α-subunit alone from Escherichia coli (Ecα-subunit) was detd. by an X-ray crystallog. anal. at 2.3 Å, which is the first report on the subunits alone from the mesophiles. The biggest difference between the structures of the Ecα-subunit alone and the α-subunit in the Stα2β2-complex (Stα-subunit) was as follows. Helix 2' in the Stα-subunit, including an active site residue (Asp60), was changed to a flexible loop in the Ecα-subunit alone. The conversion of the helix to a loop resulted in the collapse of the correct active site conformation. This region is also an important part for the mutual activation in the Stα2β2-complex and interaction with the β-subunit. These results suggest that the formation of helix 2' that is essential for the stimulation of the enzymic activity of the α-subunit is constructed by the induced-fit mode involved in conformational changes upon interaction between the α- and β-subunits. This also confirms the prediction of the conformational changes based on the thermodn. anal. for the assocn. between the α- and β-subunits.

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24. 24

    Ghosh, R. K.; Hilario, E.; Liu, V.; Wang, Y.; Niks, D.; Holmes, J. B.; Sakhrani, V. V.; Mueller, L. J.; Dunn, M. F. Mutation of βGln114 to Ala Alters the Stabilities of Allosteric States in Tryptophan Synthase Catalysis. Biochemistry 2021, 60, 3173– 3186,  DOI: 10.1021/acs.biochem.1c00383

    24

    Mutation of βGln114 to Ala Alters the Stabilities of Allosteric States in Tryptophan Synthase Catalysis

    Ghosh, Rittik K.; Hilario, Eduardo; Liu, Viktoriia; Wang, Yangyang; Niks, Dimitri; Holmes, Jacob B.; Sakhrani, Varun V.; Mueller, Leonard J.; Dunn, Michael F.

    Biochemistry (2021), 60 (42), 3173-3186CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    The tryptophan synthase (TS) bienzyme complexes found in bacteria, yeasts, and molds are pyridoxal 5'-phosphate (PLP)-requiring enzymes that synthesize L-Trp. In the TS catalytic cycle, switching between the open and closed states of the α- and β-subunits via allosteric interactions is key to the efficient conversion of 3-indole-D-glycerol-3'-phosphate and L-Ser to L-Trp. In this process, the roles played by β-site residues proximal to the PLP cofactor have not yet been fully established. βGln114 is one such residue. To explore the roles played by βQ114, the authors conducted a detailed study of the βQ114 Å mutation on the structure and function of tryptophan synthase. Initial steady-state kinetic and static UV-visible spectroscopic analyses showed the Q to A mutation impairs catalytic activity and alters the stabilities of intermediates in the β-reaction. Therefore, the authors conducted x-ray structural and solid-state NMR spectroscopic studies to compare the wild-type and βQ114 Å mutant enzymes. These comparisons establish that the protein structural changes are limited to the Gln to Ala replacement, the loss of hydrogen bonds among the side chains of βGln114, βAsn145, and βArg148, and the inclusion of waters in the cavity created by substitution of the smaller Ala side chain. Because the conformations of the open and closed allosteric states are not changed by the mutation, the authors hypothesize that the altered properties arise from the lost hydrogen bonds that alter the relative stabilities of the open (βT state) and closed (βR state) conformations of the β-subunit and consequently alter the distribution of intermediates along the β-subunit catalytic path.

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25. 25

    Marabotti, A.; De Biase, D.; Tramonti, A.; Bettati, S.; Mozzarelli, A. Allosteric Communication of Tryptophan Synthase: Functional and Regulatory Properties of the βS178P mutant. J. Biol. Chem. 2001, 276, 17747– 17753,  DOI: 10.1074/jbc.M011781200

    25

    Allosteric communication of tryptophan synthase: functional and regulatory properties of the βS178P mutant

    Marabotti, Anna; De Biase, Daniela; Tramonti, Angela; Bettati, Stefano; Mozzarelli, Andrea

    Journal of Biological Chemistry (2001), 276 (21), 17747-17753CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    The α2β2 tryptophan synthase complex is a model enzyme for understanding allosteric regulation. We report the functional and regulatory properties of the βS178P mutant. Ser-178 is located at the end of helix 6 of the β subunit, belonging to the domain involved in intersubunit signaling. The carbonyl group of βSer-178 is hydrogen bonded to Gly-181 of loop 6 of the α subunit only when α subunit ligands are bound. An anal. by mol. modeling of the structural effects caused by the βS178P mutation suggests that the hydrogen bond involving αGly-181 is disrupted as a result of localized structural perturbations. The ratio of α to β subunit concns. was calcd. to be 0.7, as for the wild type, indicating the maintenance of a tight α-β complex. Both the activity of the α subunit and the inhibitory effect of the α subunit ligands indole-3-acetylglycine and D,L-α-glycerol-3-phosphate were found to be the same for the mutant and wild type enzyme, whereas the β subunit activity of the mutant exhibited a 2-fold decrease. In striking contrast to that obsd. for the wild type, the allosteric effectors indole-3-acetylglycine and D,L-α-glycerol-3-phosphate do not affect the β activity. Accordingly, the distribution of L-serine intermediates at the β-site, dominated by the α-aminoacrylate, is only slightly influenced by α subunit ligands. Binding of sodium ions is weaker in the mutant than in the wild type and leads to a limited increase of the amt. of the external aldimine intermediate, even at high pH, whereas binding of cesium ions exhibits the same affinity and effects as in the wild type, leading to an increase of the α-aminoacrylate tautomer absorbing at 450 nm. Crystals of the βS178P mutant were grown, and their functional and regulatory properties were investigated by polarized absorption microspectrophotometry. These findings indicate that (i) the reciprocal activation of the α and β activity in the α2β2 complex with respect to the isolated subunits results from interactions that involve residues different from βSer-178 and (ii) βSer-178 is a crit. residue in ligand-triggered signals between α and β active sites.

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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXktFWntb8%253D&md5=4b650a4f8e93785db80527ce2ecf7566
26. 26

    Weyand, M.; Schlichting, I.; Herde, P.; Marabotti, A.; Mozzarelli, A. Crystal Structure of the βSer178 → Pro Mutant of Tryptophan Synthase: A “Knock-out” Allosteric Enzyme. J. Biol. Chem. 2002, 277, 10653– 10660,  DOI: 10.1074/jbc.M111031200

    26

    Crystal structure of the βSer178 → Pro mutant of tryptophan synthase: a "knock-out" allosteric enzyme

    Weyand, Michael; Schlichting, Ilme; Herde, Petra; Marabotti, Anna; Mozzarelli, Andrea

    Journal of Biological Chemistry (2002), 277 (12), 10653-10660CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    The catalytic activity of the pyridoxal 5'-phosphate-dependent tryptophan synthase α2β2 complex is allosterically regulated. The hydrogen bond between the helix βH6 residue βSer178 and the loop αL6 residue Gly181 was shown to be crit. in ligand-induced inter-subunit signaling, with the α-β communication being completely lost in the mutant βSer178 → Pro. The structural basis of the impaired allosteric regulation was investigated by detg. the crystal structures of the mutant βSer178 → Pro in the absence and presence of the α-subunit ligands indole-3-acetylglycine and glycerol 3-phosphate. The mutation causes local and distant conformational changes esp. in the β-subunit. The ligand-free structure exhibits larger differences at the N-terminal part of helix βH6, whereas the enzyme ligand complexes show differences at the C-terminal side. In contrast to the wild-type enzyme loop αL6 remains in an open conformation even in the presence of α-ligands. This effects the equil. between active and inactive conformations of the α-active site, altering kcat and Km, and forms the structural basis for the missing allosteric communication between the α- and β-subunits.

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27. 27

    Lee, T.-S.; Cerutti, D. S.; Mermelstein, D.; Lin, C.; LeGrand, S.; Giese, T. J.; Roitberg, A.; Case, D. A.; Walker, R. C.; York, D. M. GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features. J. Chem. Inf. Model. 2018, 58, 2043– 2050,  DOI: 10.1021/acs.jcim.8b00462

    27

    GPU-Accelerated Molecular Dynamics and Free Energy Methods in Amber18: Performance Enhancements and New Features

    Lee, Tai-Sung; Cerutti, David S.; Mermelstein, Dan; Lin, Charles; LeGrand, Scott; Giese, Timothy J.; Roitberg, Adrian; Case, David A.; Walker, Ross C.; York, Darrin M.

    Journal of Chemical Information and Modeling (2018), 58 (10), 2043-2050CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)

    The authors report progress in graphics processing unit (GPU)-accelerated mol. dynamics and free energy methods in Amber18. Of particular interest is the development of alchem. free energy algorithms, including free energy perturbation and thermodn. integration methods with support for nonlinear soft-core potential and parameter interpolation transformation pathways. These methods can be used in conjunction with enhanced sampling techniques such as replica exchange, const.-pH mol. dynamics, and new 12-6-4 potentials for metal ions. Addnl. performance enhancements have been made that enable appreciable speed-up on GPUs relative to the previous software release.

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28. 28

    Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kalé, L.; Schulten, K. Scalable Molecular Dynamics with NAMD. J. Comput. Chem. 2005, 26, 1781– 1802,  DOI: 10.1002/jcc.20289

    28

    Scalable molecular dynamics with NAMD

    Phillips, James C.; Braun, Rosemary; Wang, Wei; Gumbart, James; Tajkhorshid, Emad; Villa, Elizabeth; Chipot, Christophe; Skeel, Robert D.; Kale, Laxmikant; Schulten, Klaus

    Journal of Computational Chemistry (2005), 26 (16), 1781-1802CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    NAMD is a parallel mol. dynamics code designed for high-performance simulation of large biomol. systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This article, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical mol. dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temp. and pressure controls used. Features for steering the simulation across barriers and for calcg. both alchem. and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Finally, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomol. system, highlighting particular features of NAMD, for example, the Tcl scripting language. The article also provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the mol. graphics/sequence anal. software VMD and the grid computing/collab. software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.

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29. 29

    Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M. CHARMM: The biomolecular simulation program. J. Comput. Chem. 2009, 30, 1545– 1614,  DOI: 10.1002/jcc.21287

    29

    CHARMM: The biomolecular simulation program

    Brooks, B. R.; Brooks, C. L., III; Mackerell, A. D., Jr.; Nilsson, L.; Petrella, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M.

    Journal of Computational Chemistry (2009), 30 (10), 1545-1614CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    A review. CHARMM (Chem. at HARvard Mol. Mechanics) is a highly versatile and widely used mol. simulation program. It has been developed over the last three decades with a primary focus on mols. of biol. interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small mol. ligands, as they occur in soln., crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, mol. minimization, dynamics, and anal. techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calcns. with CHARMM can be performed using a no. of different energy functions and models, from mixed quantum mech.-mol. mech. force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009.

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30. 30

    Shaw, D. E.; Grossman, J. P.; Bank, J. A.; Batson, B.; Butts, J. A.; Chao, J. C.; Deneroff, M. M.; Dror, R. O.; Even, A.; Fenton, C. H.; et al. Anton 2: Raising the Bar for Performance and Programmability in a Special-Purpose Molecular Dynamics Supercomputer. SC ’14: Proceedings of the International Conference for High Performance Computing, Networking, Storage and Analysis, New Orleans, LA, USA, Nov 16–21, 2014; IEEE Press: New Orleans, LA, USA, 2014; pp. 41– 53.

    There is no corresponding record for this reference.
31. 31

    Sugita, Y.; Kamiya, M.; Oshima, H.; Re, S. Replica-Exchange Methods for Biomolecular Simulations. Methods Mol. Biol. 2019, 2022, 155– 177,  DOI: 10.1007/978-1-4939-9608-7_7

    31

    Replica-Exchange Methods for Biomolecular Simulations

    Sugita, Yuji; Kamiya, Motoshi; Oshima, Hiraku; Re, Suyong

    Methods in Molecular Biology (New York, NY, United States) (2019), 2022 (Biomolecular Simulations), 155-177CODEN: MMBIED; ISSN:1940-6029. (Springer)

    In this study, a replica-exchange method was developed to overcome conformational sampling difficulties in computer simulations of spin glass or other systems with rugged free-energy landscapes. This method was then applied to the protein-folding problem in combination with mol. dynamics (MD) simulation. Owing to its simplicity and sampling efficiency, the replica-exchange method has been applied to many other biol. problems and has been continuously improved. The method has often been combined with other sampling techniques, such as umbrella sampling, free-energy perturbation, metadynamics, and Gaussian accelerated MD (GaMD). In this chapter, we first summarize the original replica-exchange mol. dynamics (REMD) method and discuss how new algorithms related to the original method are implemented to add new features. Heterogeneous and flexible structures of an N-glycan in a soln. are simulated as an example of applications by REMD, replica exchange with solute tempering, and GaMD. The sampling efficiency of these methods on the N-glycan system and the convergence of the free-energy changes are compared. REMD simulation protocols and trajectory anal. using the GENESIS software are provided to facilitate the practical use of advanced simulation methods.

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32. 32

    Zuckerman, D. M.; Chong, L. T. Weighted Ensemble Simulation: Review of Methodology, Applications, and Software. Annu. Rev. Biophys. 2017, 46, 43– 57,  DOI: 10.1146/annurev-biophys-070816-033834

    32

    Weighted Ensemble Simulation: Review of Methodology, Applications, and Software

    Zuckerman, Daniel M.; Chong, Lillian T.

    Annual Review of Biophysics (2017), 46 (), 43-57CODEN: ARBNCV; ISSN:1936-122X. (Annual Reviews)

    The weighted ensemble (WE) methodol. orchestrates quasi-independent parallel simulations run with intermittent communication that can enhance sampling of rare events such as protein conformational changes, folding, and binding. The WE strategy can achieve superlinear scaling-the unbiased estn. of key observables such as rate consts. and equil. state populations to greater precision than would be possible with ordinary parallel simulation. WE software can be used to control any dynamics engine, such as std. mol. dynamics and cell-modeling packages. This article reviews the theor. basis of WE and goes on to describe successful applications to a no. of complex biol. processes-protein conformational transitions, (un)binding, and assembly processes, as well as cell-scale processes in systems biol. We furthermore discuss the challenges that need to be overcome in the next phase of WE methodol. development. Overall, the combined advances in WE methodol. and software have enabled the simulation of long-timescale processes that would otherwise not be practical on typical computing resources using std. simulation.

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33. 33

    Valsson, O.; Tiwary, P.; Parrinello, M. Enhancing Important Fluctuations: Rare Events and Metadynamics from a Conceptual Viewpoint. Annu. Rev. Phys. Chem. 2016, 67, 159– 184,  DOI: 10.1146/annurev-physchem-040215-112229

    33

    Enhancing Important Fluctuations: Rare Events and Metadynamics from a Conceptual Viewpoint

    Valsson, Omar; Tiwary, Pratyush; Parrinello, Michele

    Annual Review of Physical Chemistry (2016), 67 (), 159-184CODEN: ARPLAP; ISSN:0066-426X. (Annual Reviews)

    Atomistic simulations play a central role in many fields of science. However, their usefulness is often limited by the fact that many systems are characterized by several metastable states sepd. by high barriers, leading to kinetic bottlenecks. Transitions between metastable states are thus rare events that occur on significantly longer timescales than one can simulate in practice. Numerous enhanced sampling methods have been introduced to alleviate this timescale problem, including methods based on identifying a few crucial order parameters or collective variables and enhancing the sampling of these variables. Metadynamics is one such method that has proven successful in a great variety of fields. Here we review the conceptual and theor. foundations of metadynamics. As demonstrated, metadynamics is not just a practical tool but can also be considered an important development in the theory of statistical mechanics.

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34. 34

    Sugita, Y.; Okamoto, Y. Replica-exchange molecular dynamics method for protein folding. Chem. Phys. Lett. 1999, 314, 141– 151,  DOI: 10.1016/S0009-2614(99)01123-9

    34

    Replica-exchange molecular dynamics method for protein folding

    Sugita, Y.; Okamoto, Y.

    Chemical Physics Letters (1999), 314 (1,2), 141-151CODEN: CHPLBC; ISSN:0009-2614. (Elsevier Science B.V.)

    We have developed a formulation for mol. dynamics algorithm for the replica-exchange method. The effectiveness of the method for the protein-folding problem is tested with the penta-peptide Met-enkephalin. The method can overcome the multiple-min. problem by exchanging non-interacting replicas of the system at several temps. From only one simulation run, one can obtain probability distributions in canonical ensemble for a wide temp. range using multiple-histogram re-weighting techniques, which allows the calcn. of any thermodn. quantity as a function of temp. in that range.

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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXotVKrsLc%253D&md5=0fec0ff81ca7806c1e1ac29e5f50ce19
35. 35

    Sugita, Y.; Kitao, A.; Okamoto, Y. Multidimensional replica-exchange method for free-energy calculations. J. Chem. Phys. 2000, 113, 6042– 6051,  DOI: 10.1063/1.1308516

    35

    Multidimensional replica-exchange method for free-energy calculations

    Sugita, Yuji; Kitao, Akio; Okamoto, Yuko

    Journal of Chemical Physics (2000), 113 (15), 6042-6051CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    We have developed a new simulation algorithm for free-energy calcns. The method is a multidimensional extension of the replica-exchange method. While pairs of replicas with different temps. are exchanged during the simulation in the original replica-exchange method, pairs of replicas with different temps. and/or different parameters of the potential energy are exchanged in the new algorithm. This greatly enhances the sampling of the conformational space and allows accurate calcns. of free energy in a wide temp. range from a single simulation run, using the weighted histogram anal. method.

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36. 36

    Sugita, Y.; Okamoto, Y. Replica-exchange multicanonical algorithm and multicanonical replica-exchange method for simulating systems with rough energy landscape. Chem. Phys. Lett. 2000, 329, 261– 270,  DOI: 10.1016/S0009-2614(00)00999-4

    36

    Replica-exchange multicanonical algorithm and multicanonical replica-exchange method for simulating systems with rough energy landscape

    Sugita, Y.; Okamoto, Y.

    Chemical Physics Letters (2000), 329 (3,4), 261-270CODEN: CHPLBC; ISSN:0009-2614. (Elsevier Science B.V.)

    We propose two efficient algorithms for configurational sampling of systems with rough energy landscape. The first one is a new method for the detn. of the multi-canonical wt. factor. In this method, a short replica-exchange simulation is performed and the multi-canonical wt. factor is obtained by the multiple histogram reweighting techniques. The second one is a further extension of the first in which a replica-exchange multi-canonical simulation is performed with a small no. of replicas. These new algorithms are particularly useful for studying the protein folding problem.

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37. 37

    Kamiya, M.; Sugita, Y. Flexible selection of the solute region in replica exchange with solute tempering: Application to protein-folding simulations. J. Chem. Phys. 2018, 149, 72304,  DOI: 10.1063/1.5016222

    37

    Flexible selection of the solute region in replica exchange with solute tempering: Application to protein-folding simulations

    Kamiya, Motoshi; Sugita, Yuji

    Journal of Chemical Physics (2018), 149 (7), 072304/1-072304/11CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    Replica-exchange mol. dynamics (REMD) and their variants have been widely used in simulations of the biomol. structure and dynamics. Replica exchange with solute tempering (REST) is one of the methods where temp. of a pre-defined solute mol. is exchanged between replicas, while solvent temps. in all the replicas are kept const. REST greatly reduces the no. of replicas compared to the temp. REMD, while replicas at low temps. are often trapped under their conditions, interfering with the conformational sampling. Here, the authors introduce a new scheme of REST, referred to as generalized REST (gREST), where the solute region is defined as a part of a mol. or a part of the potential energy terms, such as the dihedral-angle energy term or Lennard-Jones energy term. The authors applied this new method to folding simulations of a β-hairpin (16 residues) and a Trp-cage (20 residues) in explicit water. The protein dihedral-angle energy term is chosen as the solute region in the simulations. gREST reduces the no. of replicas necessary for good random walks in the solute-temp. space and covers a wider conformational space compared to the conventional REST2. Considering the general applicability, gREST should become a promising tool for the simulations of protein folding, conformational dynamics, and an in silico drug design. (c) 2018 American Institute of Physics.

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38. 38

    Dokainish, H. M.; Sugita, Y. Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling. Int. J. Mol. Sci. 2021, 22, 270,  DOI: 10.3390/ijms22010270

    38

    Exploring large domain motions in proteins using atomistic molecular dynamics with enhanced conformational sampling

    Dokainish, Hisham M.; Sugita, Yuji

    International Journal of Molecular Sciences (2021), 22 (1), 270CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    Conformational transitions in multidomain proteins are essential for biol. functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. To simulate the transitions using atomistic mol. dynamics (MD) simulations, efficient conformational sampling algorithms are required. In this work, we propose a new approach based on generalized replica-exchange with solute tempering (gREST) for exploring the open-closed conformational changes in multidomain proteins. Wherein, selected surface charged residues in a target protein are defined as the solute region in gREST simulation and the solute temps. are different in replicas and exchanged between them to enhance the domain motions. This approach is called gREST selected surface charged residues (gREST_SSCR) and is applied to the Apo and Holo states of ribose binding protein (RBP) in soln. The conformational spaces sampled with gREST_SSCR are much wider than those with the conventional MD, sampling open-closed conformational changes while maintaining RBP domains' stability. The free-energy landscapes of RBP in the Apo and Holo states are drawn along with twist and hinge angles of the two moving domains. The inter-domain salt-bridges that are not obsd. in the exptl. structures are also important in the intermediate states during the conformational changes.

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39. 39

    Oshima, H.; Re, S.; Sugita, Y. Replica-Exchange Umbrella Sampling Combined with Gaussian Accelerated Molecular Dynamics for Free-Energy Calculation of Biomolecules. J. Chem. Theory Comput. 2019, 15, 5199– 5208,  DOI: 10.1021/acs.jctc.9b00761

    39

    Replica-Exchange Umbrella Sampling Combined with Gaussian Accelerated Molecular Dynamics for Free-Energy Calculation of Biomolecules

    Oshima, Hiraku; Re, Suyong; Sugita, Yuji

    Journal of Chemical Theory and Computation (2019), 15 (10), 5199-5208CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    We have developed an enhanced conformational sampling method combining replica-exchange umbrella sampling (REUS) with Gaussian accelerated mol. dynamics (GaMD). REUS enhances the sampling along predefined reaction coordinates, while GaMD accelerates the conformational dynamics by adding a boost potential to the system energy. The method, which we call GaREUS (Gaussian accelerated replica-exchange umbrella sampling), enhances the sampling more efficiently than REUS or GaMD, while the computational resource for GaREUS is the same as that required for REUS. The two-step reweighting procedure using the multistate Bennett acceptance ratio method and the cumulant expansion for the exponential av. is applied to the simulation trajectories for obtaining the unbiased free-energy landscapes. We apply GaREUS to the calcns. of free-energy landscapes for three different cases: conformational equil. of N-glycan, folding of chignolin, and conformational change of adenyl kinase. We show that GaREUS speeds up the convergences of free-energy calcns. using the same amt. of computational resources as REUS. The free-energy landscapes reweighted from the trajectories of GaREUS agree with previously reported ones. GaREUS is applicable to free-energy calcns. of various biomol. dynamics and functions with reasonable computational costs.

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40. 40

    Laio, A.; Parrinello, M. Escaping free-energy minima. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12562– 12566,  DOI: 10.1073/pnas.202427399

    40

    Escaping free-energy minima

    Laio, Alessandro; Parrinello, Michele

    Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (20), 12562-12566CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    We introduce a powerful method for exploring the properties of the multidimensional free energy surfaces (FESs) of complex many-body systems by means of coarse-grained non-Markovian dynamics in the space defined by a few collective coordinates. A characteristic feature of these dynamics is the presence of a history-dependent potential term that, in time, fills the min. in the FES, allowing the efficient exploration and accurate detn. of the FES as a function of the collective coordinates. We demonstrate the usefulness of this approach in the case of the dissocn. of a NaCl mol. in water and in the study of the conformational changes of a dialanine in soln.

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41. 41

    Bonomi, M.; Bussi, G.; Camilloni, C.; Tribello, G. A.; Banáč, P.; Barducci, A. Plumed consortium, Promoting transparency and reproducibility in enhanced molecular simulations. Nat. Methods 2019, 16, 670– 673,  DOI: 10.1038/s41592-019-0506-8

    There is no corresponding record for this reference.
42. 42

    Yu, I.; Mori, T.; Ando, T.; Harada, R.; Jung, J.; Sugita, Y.; Feig, M. Biomolecular Interactions Modulate Macromolecular Structure and Dynamics in Atomistic Model of a Bacterial Cytoplasm. eLife 2016, 5, 18457,  DOI: 10.7554/eLife.19274

    There is no corresponding record for this reference.
43. 43

    Jung, J.; Nishima, W.; Daniels, M.; Bascom, G.; Kobayashi, C.; Adedoyin, A.; Wall, M.; Lappala, A.; Phillips, D.; Fischer, W. Scaling molecular dynamics beyond 100,000 processor cores for large-scale biophysical simulations. J. Comput. Chem. 2019, 40, 1919– 1930,  DOI: 10.1002/jcc.25840

    43

    Scaling molecular dynamics beyond 100,000 processor cores for large-scale biophysical simulations

    Jung, Jaewoon; Nishima, Wataru; Daniels, Marcus; Bascom, Gavin; Kobayashi, Chigusa; Adedoyin, Adetokunbo; Wall, Michael; Lappala, Anna; Phillips, Dominic; Fischer, William; Tung, Chang-Shung; Schlick, Tamar; Sugita, Yuji; Sanbonmatsu, Karissa Y.

    Journal of Computational Chemistry (2019), 40 (21), 1919-1930CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    The growing interest in the complexity of biol. interactions is continuously driving the need to increase system size in biophys. simulations, requiring not only powerful and advanced hardware but adaptable software that can accommodate a large no. of atoms interacting through complex forcefields. To address this, we developed and implemented strategies in the GENESIS mol. dynamics package designed for large nos. of processors. Long-range electrostatic interactions were parallelized by minimizing the no. of processes involved in communication. A novel algorithm was implemented for nonbonded interactions to increase single instruction multiple data (SIMD) performance, reducing memory usage for ultra large systems. Memory usage for neighbor searches in real-space nonbonded interactions was reduced by approx. 80%, leading to significant speedup. Using exptl. data describing phys. 3D chromatin interactions, we constructed the first atomistic model of an entire gene locus (GATA4). Taken together, these developments enabled the first billion-atom simulation of an intact biomol. complex, achieving scaling to 65,000 processes (130,000 processor cores) with 1 ns/day performance. Published 2019. This article is a U. S. Government work and is in the public domain in the USA.

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44. 44

    Spyrakis, F.; Raboni, S.; Cozzini, P.; Bettati, S.; Mozzarelli, A. Allosteric communication between α and β subunits of tryptophan synthase: Modelling the open-closed transition of the α subunit. Biochim. Biophys. Acta 2006, 1764, 1102– 1109,  DOI: 10.1016/j.bbapap.2006.03.005

    44

    Allosteric communication between alpha and beta subunits of tryptophan synthase: Modelling the open-closed transition of the alpha subunit

    Spyrakis, Francesca; Raboni, Samanta; Cozzini, Pietro; Bettati, Stefano; Mozzarelli, Andrea

    Biochimica et Biophysica Acta, Proteins and Proteomics (2006), 1764 (6), 1102-1109CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)

    Ligand binding to the α-subunit of the α2β2 complex of tryptophan synthase induces the αloop6 closure over the α-active site. This conformational change is assocd. with the formation of a hydrogen bond between αGly181 NH group and βSer178 carbonyl oxygen, a key event for the triggering of intersubunit allosteric signals. Mutation of βSer178 to Pro and αGly181 to Pro, Ala, Phe and Val abolishes the ligand-induced intersubunit communication. Mol. dynamics methods were applied to simulate the conformation of the highly flexible and crystallog. undetectable open state of αloop6 in the wild type and in the α181 mutants. The open conformation of αloop6 is favored in the wild type enzyme in the absence of α-ligands, and in the α181 mutants both in the presence and absence of bound ligands. A very good correlation was found between the extent of limited tryptic proteolysis and both the hydrogen bond distance between αX181 and βSer178, obtained from the mol. dynamics simulation, and the hydrogen bond strength, evaluated by HINT, an empirical force field that takes into account both enthalpic and entropic contributions. Comparison of the open and closed conformations of αloop6 suggests a pathway for substrate entrance into the α-active site and provides an explanation for the limited catalytic efficiency of the open state.

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45. 45

    Fatmi, M. Q.; Ai, R.; Chang, C. A. Synergistic Regulation and Ligand-Induced Conformational Changes of Tryptophan Synthase. Biochemistry 2009, 48, 9921– 9931,  DOI: 10.1021/bi901358j

    45

    Synergistic Regulation and Ligand-Induced Conformational Changes of Tryptophan Synthase

    Fatmi, M. Qaiser; Ai, Rizi; Chang, Chia-En A.

    Biochemistry (2009), 48 (41), 9921-9931CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Conformational changes of enzyme complexes are often related to regulating and creating an optimal environment for efficient chem. The synergistic regulation of the tryptophan synthase (TRPS) complex, studied for decades as a model of allosteric regulation and substrate channeling within protein complexes, was investigated. TRPS is a bifunctional tetrameric αββα enzyme complex that exhibits cooperative motions of the α- and β-subunits by tightly controlled allosteric interactions. The atomically detailed dynamics and conformational changes of TRPS were delineated in the absence and presence of substrates using mol. dynamics simulations. The computed energy and entropy assocd. with the protein motions also offer mechanistic insights into the conformational fluctuations and the ligand binding mechanism. The flexible α-L6 loop samples both open and partially closed conformations in the ligand-free state but shifts to fully closed conformations when its substrates are present. The fully closed conformations are induced by favorable protein-ligand interactions but are partly compensated by configurational entropy loss. Considerable local rearrangements exist during ligand binding processes when the system is searching for energy min. The motion of the region that closes the β-subunit during catalysis, the COMM domain, couples with the motion of the α-subunit, although the fluctuations are smaller than in the flexible loop regions. Because of multiple conformations of ligand-free TRPS in the open and partially closed states, the α-L6 loop fluctuations have preferential directionality, which may facilitate the fully closed conformations induced by α- and β-substrates binding to both subunits. Such cooperative and directional motion may be a general feature that contributes to catalysis in many enzyme complexes.

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46. 46

    Fatmi, M. Q.; Chang, C. A. The Role of Oligomerization and Cooperative Regulation in Protein Function: The Case of Tryptophan Synthase. PLoS Comput. Biol. 2010, 6, e1000994  DOI: 10.1371/journal.pcbi.1000994

    There is no corresponding record for this reference.
47. 47

    Parveen, T.; Kamran, M.; Fatmi, M. Q. Structural and dynamical thermostability of psychrophilic enzyme at various temperatures: Molecular dynamics simulations of tryptophan synthase. Arch. Biochem. Biophys. 2019, 663, 297– 305,  DOI: 10.1016/j.abb.2019.01.022

    47

    Structural and dynamical thermostability of psychrophilic enzyme at various temperatures: Molecular dynamics simulations of tryptophan synthase

    Parveen, Tamsila; Kamran, M.; Fatmi, M. Qaiser

    Archives of Biochemistry and Biophysics (2019), 663 (), 297-305CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)

    Mesophilic enzymes are among the most frequently used biocatalysts, however, psychrophilic enzymes are crucially important for their use in heat-sensitive reactions. How enzymes can work efficiently at various range of temps. is an interesting subject for researchers, and yet it is very least explored. The structural and dynamical behavior of psychrophilic enzymes and their thermostability at various temps. can help to understand the mechanism and function at mol. level, and for this purpose the ligand-free α-subunit of Shewanella frigidimarina's tryptophan synthase (Sf-TRPS) in isolated monomeric and in hetero-αβ-dimeric states was subjected to mol. dynamics (MD) simulations study. The simulation sampled a complete open conformation of Loop L6 in α-subunit with and without β-partner, which was further investigated under three temps. mimicking psychrophilic, mesophilic and thermophilic environment. The results indicated an imperative role of β-subunit in the dynamics of L6 loop as well as in the thermostability of α-subunit by increasing interaction strength at the αβ-interface. An interesting relation was obsd. between the nos. of H-bonds and residue-pairs forming salt bridges at every temp., and the combine effect seemed to regulate the balance between protein rigidity and flexibility. The outcome of the study will help to understand the driving forces that lead to the stability of the protein at different temp., and thereby, assist in enzyme engineering that will be beneficial from industrial point of view.

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48. 48

    Maria-Solano, M. A.; Iglesias-Fernández, J.; Osuna, S. Deciphering the Allosterically Driven Conformational Ensemble in Tryptophan Synthase Evolution. J. Am. Chem. Soc. 2019, 141, 13049– 13056,  DOI: 10.1021/jacs.9b03646

    48

    Deciphering the allosterically driven conformational ensemble in tryptophan synthase evolution

    Maria-Solano, Miguel A.; Iglesias-Fernandez, Javier; Osuna, Silvia

    Journal of the American Chemical Society (2019), 141 (33), 13049-13056CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Multimeric enzyme complexes are ubiquitous in nature and catalyze a broad range of useful biol. transformations. They are often characterized by a tight allosteric coupling between subunits, making them highly inefficient when isolated. A good example is Tryptophan synthase (TrpS), an allosteric heterodimeric enzyme in the form of an αββα complex that catalyzes the biosynthesis of L-tryptophan. In this study, we decipher the allosteric regulation existing in TrpS from Pyrococcus furiosus (PfTrpS), and how the allosteric conformational ensemble is recovered in lab.-evolved stand-alone β-subunit variants. We find that recovering the conformational ensemble of a subdomain of TrpS affecting the relative stabilities of open, partially closed, and closed conformations is a prerequisite for enhancing the catalytic efficiency of the β-subunit in the absence of its binding partner. The distal mutations resuscitate the allosterically driven conformational regulation and alter the populations and rates of exchange between these multiple conformational states, which are essential for the multistep reaction pathway of the enzyme. Interestingly, these distal mutations can be a priori predicted by careful anal. of the conformational ensemble of the TrpS enzyme through computational methods. Our study provides the enzyme design field with a rational approach for evolving allosteric enzymes toward improved stand-alone function for biosynthetic applications.

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49. 49

    Zhang, D.; Lazim, R. Exploring indole channeling in tryptophan synthase using steered molecular dynamics simulation. Chem. Phys. Lett. 2019, 734, 136701,  DOI: 10.1016/j.cplett.2019.136701

    49

    Exploring indole channeling in tryptophan synthase using steered molecular dynamics simulation

    Zhang, Dawei; Lazim, Raudah

    Chemical Physics Letters (2019), 734 (), 136701CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)

    Due to the absence of tryptophan synthase (TrpS) in human, this enzyme has become a popular drug target for infectious diseases such as tuberculosis and trachoma. In this work, the channeling of indole between the two subunits of TrpS was examd. using steered mol. dynamics simulation. Through the simulations conducted, interactions between indole and residues lining the channel were scrutinized to provide insights that may be informative for the development of drugs that could potentially inhibit the enzyme.

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50. 50

    Teixeira, C. S. S.; Ramos, M. J.; Sousa, S. F.; Cerqueira, N. M. F. S. A. Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis. ChemCatChem 2020, 12, 227– 237,  DOI: 10.1002/cctc.201901505

    50

    Solving the catalytic mechanism of tryptophan synthase: an emergent drug target in the treatment of tuberculosis

    Teixeira, Carla S. Silva; Ramos, Maria J.; Sousa, Sergio F.; Cerqueira, Nuno M. F. S. A.

    ChemCatChem (2020), 12 (1), 227-237CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis, it catalyzes the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the at. level. The fact that TSase is a multifunctional enzyme, with two dimers, each one with two independent active sites, interconnected by a 25 Å tunnel, has made it a challenging enzyme, from the catalytic point of view. QM/MM calcns. were used to analyze and explain the two steps catalyzed by this enzyme. The results provide an at.-level clarification of the full catalytic mechanism of this enzyme, offering also important clues for the development of new inhibitors against tuberculosis.

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51. 51

    Torrie, G. M.; Valleau, J. P. Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling. J. Comput. Phys. 1977, 23, 187– 199,  DOI: 10.1016/0021-9991(77)90121-8

    There is no corresponding record for this reference.
52. 52

    Coutsias, E. A.; Seok, C.; Jacobson, M. P.; Dill, K. A. A kinematic view of loop closure. J. Comput. Chem. 2004, 25, 510– 528,  DOI: 10.1002/jcc.10416

    52

    A kinematic view of loop closure

    Coutsias, Evangelos A.; Seok, Chaok; Jacobson, Matthew P.; Dill, Ken A.

    Journal of Computational Chemistry (2004), 25 (4), 510-528CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    We consider the problem of loop closure, i.e., of finding the ensemble of possible backbone structures of a chain segment of a protein mol. that is geometrically consistent with preceding and following parts of the chain whose structures are given. We reduce this problem of detg. the loop conformations of six torsions to finding the real roots of a 16th degree polynomial in one variable, based on the robotics literature on the kinematics of the equiv. rotator linkage in the most general case of oblique rotators. We provide a simple intuitive view and derivation of the polynomial for the case in which each of the three pair of torsional axes has a common point. Our method generalizes previous work on anal. loop closure in that the torsion angles need not be consecutive, and any rigid intervening segments are allowed between the free torsions. Our approach also allows for a small degree of flexibility in the bond angles and the peptide torsion angles; this substantially enlarges the space of solvable configurations as is demonstrated by an application of the method to the modeling of cyclic pentapeptides. We give further applications to two important problems. First, we show that this anal. loop closure algorithm can be efficiently combined with an existing loop-construction algorithm to sample loops longer than three residues. Second, we show that Monte Carlo minimization is made severalfold more efficient by employing the local moves generated by the loop closure algorithm, when applied to the global minimization of an eight-residue loop. Our loop closure algorithm is freely available at http://dillgroup. ucsf.edu/loop_closure/.

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53. 53

    Jo, S.; Kim, T.; Iyer, V. G.; Im, W. CHARMM-GUI: A web-based graphical user interface for CHARMM. J. Comput. Chem. 2008, 29, 1859– 1865,  DOI: 10.1002/jcc.20945

    53

    CHARMM-GUI: a web-based graphical user interface for CHARMM

    Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.; Im, Wonpil

    Journal of Computational Chemistry (2008), 29 (11), 1859-1865CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    CHARMM is an academic research program used widely for macromol. mechanics and dynamics with versatile anal. and manipulation tools of at. coordinates and dynamics trajectories. CHARMM-GUI, http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate various input files and mol. systems to facilitate and standardize the usage of common and advanced simulation techniques in CHARMM. The web environment provides an ideal platform to build and validate a mol. model system in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the previous setup and regenerate the whole system again. In this article, we describe the currently available functional modules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future directions of the CHARMM-GUI development project are also discussed briefly together with other features in the CHARMM-GUI website, such as Archive and Movie Gallery.

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54. 54

    Maier, J. A.; Martinez, C.; Kasavajhala, K.; Wickstrom, L.; Hauser, K. E.; Simmerling, C. ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J. Chem. Theory Comput. 2015, 11, 3696– 3713,  DOI: 10.1021/acs.jctc.5b00255

    54

    ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

    Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik; Wickstrom, Lauren; Hauser, Kevin E.; Simmerling, Carlos

    Journal of Chemical Theory and Computation (2015), 11 (8), 3696-3713CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    Mol. mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Av. errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of φ and ψ parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a phys. motivated adjustment to the φ rotational profile that compensates for lack of ff99SB QM training data in the β-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reprodn. of NMR χ1 scalar coupling measurements for proteins in soln. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements.

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55. 55

    Wang, J.; Wolf, R. M.; Caldwell, J. W.; Kollman, P. A.; Case, D. A. Development and testing of a general amber force field. J. Comput. Chem. 2004, 25, 1157– 1174,  DOI: 10.1002/jcc.20035

    55

    Development and testing of a general Amber force field

    Wang, Junmei; Wolf, Romain M.; Caldwell, James W.; Kollman, Peter A.; Case, David A.

    Journal of Computational Chemistry (2004), 25 (9), 1157-1174CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)

    We describe here a general Amber force field (GAFF) for org. mols. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most org. and pharmaceutical mols. that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited no. of atom types, but incorporates both empirical and heuristic models to est. force consts. and partial at. charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallog. structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 Å, which is comparable to that of the Tripos 5.2 force field (0.25 Å) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 Å, resp.). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermol. energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 Å and 1.2 kcal/mol, resp. These data are comparable to results from Parm99/RESP (0.16 Å and 1.18 kcal/mol, resp.), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to expt.) is about 0.5 kcal/mol. GAFF can be applied to wide range of mols. in an automatic fashion, making it suitable for rational drug design and database searching.

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56. 56

    He, X.; Man, V. H.; Yang, W.; Lee, T.-S.; Wang, J. A fast and high-quality charge model for the next generation general AMBER force field. J. Chem. Phys. 2020, 153, 114502,  DOI: 10.1063/5.0019056

    56

    A fast and high-quality charge model for the next generation general AMBER force field

    He, Xibing; Man, Viet H.; Yang, Wei; Lee, Tai-Sung; Wang, Junmei

    Journal of Chemical Physics (2020), 153 (11), 114502CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    The General AMBER Force Field (GAFF) has been broadly used by researchers all over the world to perform in silico simulations and modelings on diverse scientific topics, esp. in the field of computer-aided drug design whose primary task is to accurately predict the affinity and selectivity of receptor-ligand binding. The at. partial charges in GAFF and the second generation of GAFF (GAFF2) were originally developed with the quantum mechanics derived restrained electrostatic potential charge, but in practice, users usually adopt an efficient charge method, Austin Model 1-bond charge corrections (AM1-BCC), based on which, without expensive ab initio calcns., the at. charges could be efficiently and conveniently obtained with the ANTECHAMBER module implemented in the AMBER software package. In this work, we developed a new set of BCC parameters specifically for GAFF2 using 442 neutral org. solutes covering diverse functional groups in aq. soln. Compared to the original BCC parameter set, the new parameter set significantly reduced the mean unsigned error (MUE) of hydration free energies from 1.03 kcal/mol to 0.37 kcal/mol. More excitingly, this new AM1-BCC model also showed excellent performance in the solvation free energy (SFE) calcn. on diverse solutes in various org. solvents across a range of different dielec. consts. In this large-scale test with totally 895 neutral org. solvent-solute systems, the new parameter set led to accurate SFE predictions with the MUE and the root-mean-square-error of 0.51 kcal/mol and 0.65 kcal/mol, resp. This newly developed charge model, ABCG2, paved a promising path for the next generation GAFF development. (c) 2020 American Institute of Physics.

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57. 57

    Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graphics 1996, 14, 33– 38,  DOI: 10.1016/0263-7855(96)00018-5

    57

    VDM: visual molecular dynamics

    Humphrey, William; Dalke, Andrew; Schulten, Klaus

    Journal of Molecular Graphics (1996), 14 (1), 33-8, plates, 27-28CODEN: JMGRDV; ISSN:0263-7855. (Elsevier)

    VMD is a mol. graphics program designed for the display and anal. of mol. assemblies, in particular, biopolymers such as proteins and nucleic acids. VMD can simultaneously display any no. of structures using a wide variety of rendering styles and coloring methods. Mols. are displayed as one or more "representations," in which each representation embodies a particular rendering method and coloring scheme for a selected subset of atoms. The atoms displayed in each representation are chosen using an extensive atom selection syntax, which includes Boolean operators and regular expressions. VMD provides a complete graphical user interface for program control, as well as a text interface using the Tcl embeddable parser to allow for complex scripts with variable substitution, control loops, and function calls. Full session logging is supported, which produces a VMD command script for later playback. High-resoln. raster images of displayed mols. may be produced by generating input scripts for use by a no. of photorealistic image-rendering applications. VMD has also been expressly designed with the ability to animate mol. dynamics (MD) simulation trajectories, imported either from files or from a direct connection to a running MD simulation. VMD is the visualization component of MDScope, a set of tools for interactive problem solving in structural biol., which also includes the parallel MD program NAMD, and the MDCOMM software used to connect the visualization and simulation programs, VMD is written in C++, using an object-oriented design; the program, including source code and extensive documentation, is freely available via anonymous ftp and through the World Wide Web.

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58. 58

    The PyMOL Molecular Graphics System, Version 2.5, Schrödinger: LLC, 2021.

    There is no corresponding record for this reference.
59. 59

    Bussi, G.; Donadio, D.; Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007, 126, 014101  DOI: 10.1063/1.2408420

    59

    Canonical sampling through velocity rescaling

    Bussi, Giovanni; Donadio, Davide; Parrinello, Michele

    Journal of Chemical Physics (2007), 126 (1), 014101/1-014101/7CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    The authors present a new mol. dynamics algorithm for sampling the canonical distribution. In this approach the velocities of all the particles are rescaled by a properly chosen random factor. The algorithm is formally justified and it is shown that, in spite of its stochastic nature, a quantity can still be defined that remains const. during the evolution. In numerical applications this quantity can be used to measure the accuracy of the sampling. The authors illustrate the properties of this new method on Lennard-Jones and TIP4P water models in the solid and liq. phases. Its performance is excellent and largely independent of the thermostat parameter also with regard to the dynamic properties.

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60. 60

    Tuckerman, M.; Berne, B. J.; Martyna, G. J. Reversible multiple time scale molecular dynamics. J. Chem. Phys. 1992, 97, 1990– 2001,  DOI: 10.1063/1.463137

    60

    Reversible multiple time scale molecular dynamics

    Tuckerman, M.; Berne, B. J.; Martyna, G. J.

    Journal of Chemical Physics (1992), 97 (3), 1990-2001CODEN: JCPSA6; ISSN:0021-9606.

    The Trotter factorization of the Liouville propagator is used to generate new reversible mol. dynamics integrators. This strategy is applied to derive reversible ref. system propagator algorithms (RESPA) that greatly accelerate simulations of systems with a sepn. of time scales or with long range forces. The new algorithms have all of the advantages of previous RESPA integrators but are reversible, and more stable than those methods. These methods are applied to a set of paradigmatic systems and are shown to be superior to earlier methods. It is shown how the new RESPA methods are related to predictor-corrector integrators. These methods can be used to accelerate the integration of the equations of motion of systems with Nose thermostats.

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61. 61

    Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: AnN·log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993, 98, 10089– 10092,  DOI: 10.1063/1.464397

    61

    Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems

    Darden, Tom; York, Darrin; Pedersen, Lee

    Journal of Chemical Physics (1993), 98 (12), 10089-92CODEN: JCPSA6; ISSN:0021-9606.

    An N·log(N) method for evaluating electrostatic energies and forces of large periodic systems is presented. The method is based on interpolation of the reciprocal space Ewald sums and evaluation of the resulting convolution using fast Fourier transforms. Timings and accuracies are presented for three large cryst. ionic systems.

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62. 62

    Essmann, U.; Perera, L.; Berkowitz, M. L.; Darden, T.; Lee, H.; Pedersen, L. G. A smooth particle mesh Ewald method. J. Chem. Phys. 1995, 103, 8577– 8593,  DOI: 10.1063/1.470117

    62

    A smooth particle mesh Ewald method

    Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L.; Darden, Tom; Lee, Hsing; Pedersen, Lee G.

    Journal of Chemical Physics (1995), 103 (19), 8577-93CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    The previously developed particle mesh Ewald method is reformulated in terms of efficient B-spline interpolation of the structure factors. This reformulation allows a natural extension of the method to potentials of the form 1/rp with p ≥ 1. Furthermore, efficient calcn. of the virial tensor follows. Use of B-splines in the place of Lagrange interpolation leads to analytic gradients as well as a significant improvement in the accuracy. The authors demonstrate that arbitrary accuracy can be achieved, independent of system size N, at a cost that scales as N log(N). For biomol. systems with many thousands of atoms and this method permits the use of Ewald summation at a computational cost comparable to that of a simple truncation method of 10 Å or less.

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63. 63

    Andersen, H. C. Rattle: A “velocity” version of the shake algorithm for molecular dynamics calculations. J. Comput. Phys. 1983, 52, 24– 34,  DOI: 10.1016/0021-9991(83)90014-1

    63

    RATTLE: a "velocity" version of the SHAKE algorithm for molecular dynamics calculations

    Andersen, Hans C.

    Journal of Computational Physics (1983), 52 (1), 24-34CODEN: JCTPAH; ISSN:0021-9991.

    An algorithm, called RATTLE, for integrating the equations of motion in mol. dynamics calcns. for mol. models with internal constraints is presented. RATTLE calcs. the positions and velocities at the next time from the positions and velocities at the present time step, without requiring information about the earlier history. It is based on the Verlet algorithm and retains the simplicity of using Cartesian coordinates for each of the atoms to describe the configuration of a mol. with internal constraints. RATTLE guarantees that the coordinates and velocities of the atoms in a mol. satisfy the internal constraints at each time step.

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64. 64

    Miyamoto, S.; Kollman, P. A. Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. J. Comput. Chem. 1992, 13, 952– 962,  DOI: 10.1002/jcc.540130805

    64

    SETTLE: an analytical version of the SHAKE and RATTLE algorithm for rigid water models

    Miyamoto, Shuichi; Kollman, Peter A.

    Journal of Computational Chemistry (1992), 13 (8), 952-62CODEN: JCCHDD; ISSN:0192-8651.

    An anal. algorithm, called SETTLE, for resetting the positions and velocities to satisfy the holonomic constraints on the rigid water model is presented. This method is based on the Cartesian coordinate system and can be used in place of SHAKE and RATTLE. The authors implemented this algorithm in the SPASMS package of mol. mechanics and dynamics. Several series of mol. dynamics simulations were carried out to examine the performance of the new algorithm in comparison with the original RATTLE method. SETTLE is of higher accuracy and is faster than RATTLE with reasonable tolerances by three to nine times on a scalar machine. The performance improvement ranged from factors of 26 to 98 on a vector machine since the method presented is not iterative.

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65. 65

    Jung, J.; Kasahara, K.; Kobayashi, C.; Oshima, H.; Mori, T.; Sugita, Y. Optimized Hydrogen Mass Repartitioning Scheme Combined with Accurate Temperature/Pressure Evaluations for Thermodynamic and Kinetic Properties of Biological Systems. J. Chem. Theory Comput. 2021, 17, 5312– 5321,  DOI: 10.1021/acs.jctc.1c00185

    65

    Optimized Hydrogen Mass Repartitioning Scheme Combined with Accurate Temperature/Pressure Evaluations for Thermodynamic and Kinetic Properties of Biological Systems

    Jung, Jaewoon; Kasahara, Kento; Kobayashi, Chigusa; Oshima, Hiraku; Mori, Takaharu; Sugita, Yuji

    Journal of Chemical Theory and Computation (2021), 17 (8), 5312-5321CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)

    In recent years, mol. dynamics (MD) simulations with larger time steps have been performed with the hydrogen-mass-repartitioning (HMR) scheme, where the mass of each hydrogen atom is increased to reduce high-frequency motion while the mass of a non-hydrogen atom bonded to a hydrogen atom is decreased to keep the total mol. mass unchanged. Here, we optimize the scaling factors in HMR and combine them with previously developed accurate temp./pressure evaluations. The heterogeneous HMR scaling factors are useful to avoid the structural instability of amino acid residues having a five- or six-membered ring in MD simulations with larger time steps. It also reproduces kinetic properties, namely translational and rotational diffusions, if the HMR scaling factors are applied to only solute mols. The integration scheme is tested for biol. systems that include sol./membrane proteins and lipid bilayers for about 200μs MD simulations in total and give consistent results in MD simulations with both a small time step of 2.0 fs and a large, multiple time step integration with time steps of 3.5 fs (for fast motions) and 7.0 fs (for slower motions). We also confirm that the multiple time step integration scheme used in this study provides more accurate energy conservations than the RESPA/C1 and is comparable to the RESPA/C2 in NAMD. In summary, the current integration scheme combining the optimized HMR with accurate temp./pressure evaluations can provide stable and reliable MD trajectories with a larger time step, which are computationally more than 2-fold efficient compared to the conventional methods.

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66. 66

    Shirts, M. R.; Chodera, J. D. Statistically optimal analysis of samples from multiple equilibrium states. J. Chem. Phys. 2008, 129, 124105,  DOI: 10.1063/1.2978177

    66

    Statistically optimal analysis of samples from multiple equilibrium states

    Shirts, Michael R.; Chodera, John D.

    Journal of Chemical Physics (2008), 129 (12), 124105/1-124105/10CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)

    We present a new estimator for computing free energy differences and thermodn. expectations as well as their uncertainties from samples obtained from multiple equil. states via either simulation or expt. The estimator, which we call the multistate Bennett acceptance ratio estimator (MBAR) because it reduces to the Bennett acceptance ratio estimator (BAR) when only two states are considered, has significant advantages over multiple histogram reweighting methods for combining data from multiple states. It does not require the sampled energy range to be discretized to produce histograms, eliminating bias due to energy binning and significantly reducing the time complexity of computing a soln. to the estg. equations in many cases. Addnl., an est. of the statistical uncertainty is provided for all estd. quantities. In the large sample limit, MBAR is unbiased and has the lowest variance of any known estimator for making use of equil. data collected from multiple states. We illustrate this method by producing a highly precise est. of the potential of mean force for a DNA hairpin system, combining data from multiple optical tweezer measurements under const. force bias. (c) 2008 American Institute of Physics.

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67. 67

    Chovancova, E.; Pavelka, A.; Benes, P.; Strnad, O.; Brezovsky, J.; Kozlikova, B.; Gora, A.; Sustr, V.; Klvana, M.; Medek, P. CAVER 3.0: A Tool for the Analysis of Transport Pathways in Dynamic Protein Structures. PLoS Comput. Biol. 2012, 8, e1002708,  DOI: 10.1371/journal.pcbi.1002708

    67

    CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures

    Chovancova, Eva; Pavelka, Antonin; Benes, Petr; Strnad, Ondrej; Brezovsky, Jan; Kozlikova, Barbora; Gora, Artur; Sustr, Vilem; Klvana, Martin; Medek, Petr; Biedermannova, Lada; Sochor, Jiri; Damborsky, Jiri

    PLoS Computational Biology (2012), 8 (10), e1002708CODEN: PCBLBG; ISSN:1553-7358. (Public Library of Science)

    Tunnels and channels facilitate the transport of small mols., ions and water solvent in a large variety of proteins. Characteristics of individual transport pathways, including their geometry, physico-chem. properties and dynamics are instrumental for understanding of structure-function relationships of these proteins, for the design of new inhibitors and construction of improved biocatalysts. CAVER is a software tool widely used for the identification and characterization of transport pathways in static macromol. structures. Herein we present a new version of CAVER enabling automatic anal. of tunnels and channels in large ensembles of protein conformations. CAVER 3.0 implements new algorithms for the calcn. and clustering of pathways. A trajectory from a mol. dynamics simulation serves as the typical input, while detailed characteristics and summary statistics of the time evolution of individual pathways are provided in the outputs. To illustrate the capabilities of CAVER 3.0, the tool was applied for the anal. of mol. dynamics simulation of the microbial enzyme haloalkane dehalogenase DhaA. CAVER 3.0 safely identified and reliably estd. the importance of all previously published DhaA tunnels, including the tunnels closed in DhaA crystal structures. Obtained results clearly demonstrate that anal. of mol. dynamics simulation is essential for the estn. of pathway characteristics and elucidation of the structural basis of the tunnel gating. CAVER 3.0 paves the way for the study of important biochem. phenomena in the area of mol. transport, mol. recognition and enzymic catalysis. The software is freely available as a multiplatform command-line application online.

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68. 68

    Barends, T. R. M.; Domratcheva, T.; Kulik, V.; Blumenstein, L.; Niks, D.; Dunn, M. F.; Schlichting, I. Structure and Mechanistic Implications of a Tryptophan Synthase Quinonoid Intermediate. ChemBioChem 2008, 9, 1024– 1028,  DOI: 10.1002/cbic.200700703

    68

    Structure and mechanistic implications of a tryptophan synthase quinonoid intermediate

    Barends, Thomas R. M.; Domratcheva, Tatiana; Kulik, Victor; Blumenstein, Lars; Niks, Dimitri; Dunn, Michael F.; Schlichting, Ilme

    ChemBioChem (2008), 9 (7), 1024-1028CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Quinonoid intermediates play a key role in the catalytic mechanism of pyridoxal 5'-phosphate (PLP)-dependent enzymes. Whereas structures of other PLP-bound reaction intermediates have been detd., a high-quality structure of a quinonoid species has not been reported. We present the crystal structure of the indoline quinonoid intermediate of tryptophan synthase and discuss its implications for the enzymic mechanism and allosteric regulation.

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69. 69

    Lai, J.; Niks, D.; Wang, Y.; Domratcheva, T.; Barends, T. R. M.; Schwarz, F.; Olsen, R. A.; Elliott, D. W.; Fatmi, M. Q.; Chang, C. A. X-ray and NMR Crystallography in an Enzyme Active Site: The Indoline Quinonoid Intermediate in Tryptophan Synthase. J. Am. Chem. Soc. 2011, 133, 4– 7,  DOI: 10.1021/ja106555c

    69

    X-ray and NMR Crystallography in an Enzyme Active Site: The Indoline Quinonoid Intermediate in Tryptophan Synthase

    Lai, Jin-Feng; Niks, Dimitri; Wang, Ya-Chong; Domratcheva, Tatiana; Barends, Thomas R. M.; Schwarz, Friedrich; Olsen, Ryan A.; Elliott, Douglas W.; Fatmi, M. Qaiser; Chang, Chia-En A.; Schlichting, Ilme; Dunn, Michael F.; Mueller, Leonard J.

    Journal of the American Chemical Society (2011), 133 (1), 4-7CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Chem.-level details such as protonation and hybridization state are crit. for understanding enzyme mechanism and function. Even at high resoln., these details are difficult to det. by x-ray crystallog. alone. The chem. shift in NMR spectroscopy, however, is an extremely sensitive probe of the chem. environment, making solid-state NMR spectroscopy and x-ray crystallog. a powerful combination for defining chem. detailed three-dimensional structures. Here we adopted this combined approach to det. the chem. rich crystal structure of the indoline quinonoid intermediate in the pyridoxal-5'-phosphate-dependent enzyme tryptophan synthase under conditions of active catalysis. Models of the active site were developed using a synergistic approach in which the structure of this reactive substrate analog was optimized using ab initio computational chem. in the presence of side-chain residues fixed at their crystallog. detd. coordinates. Various models of charge and protonation state for the substrate and nearby catalytic residues could be uniquely distinguished by their calcd. effects on the chem. shifts measured at specifically 13C- and 15N-labeled positions on the substrate. Our model suggests the importance of an equil. between tautomeric forms of the substrate, with the protonation state of the major isomer directing the next catalytic step.

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70. 70

    Yagi, K.; Ito, S.; Sugita, Y. Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations. J. Phys. Chem. B 2021, 125, 4701– 4713,  DOI: 10.1021/acs.jpcb.1c01862

    70

    Exploring the Minimum-Energy Pathways and Free-Energy Profiles of Enzymatic Reactions with QM/MM Calculations

    Yagi, Kiyoshi; Ito, Shingo; Sugita, Yuji

    Journal of Physical Chemistry B (2021), 125 (18), 4701-4713CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Understanding mol. mechanisms of enzymic reactions is of vital importance in biochem. and biophysics. Here, the authors introduce new functions of hybrid quantum mech./mol. mech. (QM/MM) calcns. in the GENESIS program to compute the min.-energy pathways (MEPs) and free-energy profiles of enzymic reactions. For this purpose, an interface in GENESIS is developed to use a highly parallel electronic structure program, QSimulate-QM (https://qsimulate.com), calling it as a shared library from GENESIS. Second, algorithms to search the MEP are implemented, combining the string method with the energy minimization of the buffer MM region. The method implemented in GENESIS is applied to an enzyme, triosephosphate isomerase, which converts dihyroxyacetone phosphate to glyceraldehyde 3-phosphate in four proton-transfer processes. QM/MM-mol. dynamics simulations show performances of >1 ns/day with the d. functional tight binding (DFTB), and 10-30 ps/day with the hybrid d. functional theory, B3LYP-D3. These performances allow the authors to compute not only MEP but also the potential of mean force (PMF) of the enzymic reactions using the QM/MM calcns. The barrier height obtained as 13 kcal mol-1 with B3LYP-D3 in the QM/MM calcn. is in agreement with the exptl. results. The impact of conformational sampling in PMF calcns. and the level of electronic structure calcns. (DFTB vs. B3LYP-D3) suggests reliable computational protocols for enzymic reactions without high computational costs.

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