Mechanistic Insight into the Role of Transition-State Stabilization in Cyclophilin A
Abstract
Peptidyl prolyl cis−trans isomerases (PPIases) are ubiquitous enzymes in biology that catalyze the cis−trans isomerization of the proline imide peptide bond in many cell signaling pathways. The local change of the isomeric state of the prolyl peptide bond acts as a switching mechanism in altering the conformation of proteins. A complete understanding of the mechanism of PPIases is still lacking, and current experimental techniques have not been able to provide a detailed atomistic picture. Here we have carried out several accelerated molecular dynamics simulations with explicit solvent, and we have provided a detailed description of cis−trans isomerization of the free and cyclophilin A-catalyzed process. We show that the catalytic mechanism of cyclophilin is due mainly to the stabilization and preferential binding of the transition state that is achieved by a favorable hydrogen bond interaction with a backbone NH group. We also show that the substrate in the transition state interacts more favorably with the enzyme than the cis isomer, which in turn interacts more favorably than the trans isomer. The stability of the enzyme−substrate complex is directly correlated with the interaction the substrate makes with a highly conserved arginine residue. Finally, we show that catalysis is achieved through the rotation of the carbonyl oxygen on the N-terminal of the prolyl peptide bond in a predominately unidirectional fashion.
Introduction
Results and Discussions
Simulation of the Catalytic Process of cis−trans Isomerization
Stabilization of the Transition State
Role of the Highly Conserved Arginine 55
Conclusions
Computational Methods
Acknowledgment
This work was supported in part by grants to D.H. from the Georgia Cancer Coalition (GCC) and Department of Chemistry at Georgia State University, and grants to J.A.M from NSF, NIH, the NSF Center for Theoretical Biological Physics, and the National Biomedical Computation Resource. We acknowledge computer time at NSF Supercomputer Centers. This work was also supported by Georgia State’s IBM System p5 supercomputer, acquired through a partnership of the Southeastern Universities Research Association and IBM supporting the SURAgrid initiative. D.H. thanks Victor Bolet for assistance in accessing the supercomputer at Georgia State University.
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17Eberhardt, E. S., Loh, S. N., Hinck, A. P., and Raines, R. T. J. Am. Chem. Soc. 1992 114 5437 543917https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XktVyntLs%253D&md5=438a3c823ae7d021609e87496a1a9085Solvent effects on the energetics of prolyl peptide bond isomerizationEberhardt, Eric S.; Loh, Stewart N.; Hinck, Andrew P.; Raines, Ronald T.Journal of the American Chemical Society (1992), 114 (13), 5437-9CODEN: JACSAT; ISSN:0002-7863.Racemic Ac-Gly-[β,δ-13C]Pro-OMe was synthesized, and the kinetics and thermodn. of the isomerization of its prolyl peptide bond were detd. in nine solvents by NMR and IR. The free energy of activation is 1.3 kcal/mol larger in water than in aprotic solvents, and correlates with the ability of a solvent to donate a hydrogen bond but not with solvent polarity. These results are consistent with conventional pictures of amide resonance, which require transfer of charge between oxygen and nitrogen during isomerization. Similar medium effects may modulate the stability of planar peptide bonds in the active site of peptidyl-prolyl cis-trans isomerases (PPIases) and during the folding, function, or lysis of proteins.
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18Kramer, M. L., and Fischer, G. Biopolymers 1997 42 49 60There is no corresponding record for this reference.
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19Hamelberg, D., Shen, T. Y., and McCammon, J. A. J. Chem. Phys. 2006 125094905There is no corresponding record for this reference.
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20Hamelberg, D., and McCammon, J. A. J. Am. Chem. Soc. 2005 127 13778 13779There is no corresponding record for this reference.
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21Shi, T. S., Spain, S. M., and Rabenstein, D. L. J. Am. Chem. Soc. 2004 126 790 796There is no corresponding record for this reference.
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22Adcock, S. A., and McCammon, J. A. Chem Rev 2006 106 1589 615There is no corresponding record for this reference.
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23Trzesniak, D., and Van Gunsteren, W. F. Protein Sci. 2006 15 2544 255123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFygsrfJ&md5=34a981a02d67f44cf3762722a44ab4ebCatalytic mechanism of cyclophilin as observed in molecular dynamics simulations: pathway prediction and reconciliation of X-ray crystallographic and NMR solution dataTrzesniak, Daniel; Van Gunsteren, Wilfred F.Protein Science (2006), 15 (11), 2544-2551CODEN: PRCIEI; ISSN:0961-8368. (Cold Spring Harbor Laboratory Press)Cyclophilins are proteins that catalyze X-proline cis-trans interconversion, where X represents any amino acid. Its mechanism of action has been investigated over the past years but still generates discussion, esp. because until recently structures of the ligand in the cis and trans conformations for the same system were lacking. X-ray crystallog. structures for the complex cyclophilin A and HIV-1 capsid mutants with ligands in the cis and trans conformations suggest a mechanism where the N-terminal portion of the ligand rotates during the cis-trans isomerization. However, a few years before, a C-terminal rotating ligand was proposed to explain NMR soln. data. In the present study we use mol. dynamics (MD) simulations to generate a trans structure starting from the cis structure. From simulations starting from the cis and trans structures obtained through the rotational pathways, the seeming contradiction between the two sets of exptl. data could be resolved. The simulated N-terminal rotated trans structure shows good agreement with the equiv. crystal structure and, moreover, is consistent with the NMR data. These results illustrate the use of MD simulation at at. resoln. to model structural transitions and to interpret exptl. data.
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29Vajdos, F. E., Yoo, S. H., Houseweart, M., Sundquist, W. I., and Hill, C. P. Protein Sci. 1997 6 2297 230729https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnsVemu7o%253D&md5=7b2235e4a5ef90727886363f8e95868fCrystal structure of cyclophilin A complexed with a binding site peptide from the HIV-1 capsid proteinVajdos, Felix F.; Yoo, Sanghee; Houseweart, Megan; Sundquist, Wesley I.; Hill, Christopher P.Protein Science (1997), 6 (11), 2297-2307CODEN: PRCIEI; ISSN:0961-8368. (Cambridge University Press)The cellular protein, cyclophilin A (CypA), is incorporated into the virion of the type 1 human immunodeficiency virus (HIV-1) via a direct interaction with the capsid domain of the viral Gag polyprotein. We demonstrate that the capsid sequence 87His-Ala-Gly-Pro-Ile-Ala92 (87HAGPIA92) encompasses the primary cyclophilin A binding site and present an x-ray crystal structure of the CypA/HAGPIA complex. In contrast to the cis prolines obsd. in all previously reported structures of CypA complexed with model peptides, the proline in this peptide, Pro 90, binds the cyclophilin A active site in a trans conformation. We also report the crystal structure of a complex between CypA and the hexapeptide HVGPIA, which also maintains the trans conformation. Comparison with the recently detd. structures of CypA in complexes with larger fragments of the HIV-1 capsid protein demonstrates that CypA recognition of these hexapeptides involves contacts with peptide residues Ala(Val) 88, Gly 89, and Pro 90, and is independent of the context of longer sequences.
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30Zhao, Y. D., Chen, Y. Q., Schutkowski, M., Fischer, G., and Ke, H. M. Structure 1997 5 139 146There is no corresponding record for this reference.
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31McCammon, J. A., Wolynes, P. G., and Karplus, M. Biochemistry 1979 18 927 94231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhtlCns70%253D&md5=5a7c51a46bd096998cf1414f43040114Picosecond dynamics of tyrosine side chains in proteinsMcCammon, J. Andrew; Wolynes, Peter G.; Karplus, MartinBiochemistry (1979), 18 (6), 927-42CODEN: BICHAW; ISSN:0006-2960.To probe the details of small amplitude motions in proteins, a dynamical anal. of the orientation fluctuations of 2 tyrosine side chains in the bovine pancreatic trypsin inhibitor is presented. Detailed results are given for the time history and correlation functions obtained for the ring motion from a mol. dynamics simulation of the entire protein. Even on a ps time scale orientational fluctuations of ±30° from the av. position occur for the tyrosine rings in the interior of the protein. The Langevin equation is applicable to the ring torsional motion, which corresponds to that of an angular harmonic oscillator with near-crit. damping. Two possible microscopic models for the obsd. damping effects are outlined. One of these, analogous to liq. behavior, is based on kinetic theory and takes account of the collisions which occur between atoms of the protein; the other, more analogous to solid behavior, involves the coupling among a large no. of harmonic oscillators. The collisional model with parameters obtained from theor. ests. leads to good agreement with the correlation functions from the dynamic simulation. However, the dephasing of harmonic oscillations can yield similar short-time results so that a distinction between the 2 models is difficult. The importance of damping effects on the motions involved in conformational transitions and enzymic reactions is discussed.
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32Howard, B. R., Vajdos, F. F., Li, S., Sundquist, W. I., and Hill, C. P. Nat. Struct. Biol. 2003 10 475 481There is no corresponding record for this reference.
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33Eisenmesser, E. Z., Bosco, D. A., Akke, M., and Kern, D. Science 2002 295 1520 152333https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhsFyqtbw%253D&md5=834528acfd39865d81b5341e43dc1ab1Enzyme dynamics during catalysisEisenmesser, Elan Zohar; Bosco, Daryl A.; Akke, Mikael; Kern, DorotheeScience (Washington, DC, United States) (2002), 295 (5559), 1520-1523CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Internal protein dynamics are intimately connected to enzymic catalysis. However, enzyme motions linked to substrate turnover remain largely unknown. Here, the authors studied the dynamics of an enzyme during catalysis at at. resoln. using NMR relaxation methods. During catalytic action of cyclophilin A/peptidylprolyl cis-trans isomerase, the authors detected conformational fluctuations of the active site that occurred on a time scale of hundreds of microseconds. The rates of conformational dynamics of the enzyme strongly correlated with the microscopic rates of substrate turnover. The present results, together with available structural data, allowed a prediction of the reaction trajectory.
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34Kern, D., Kern, G., Scherer, G., Fischer, G., and Drakenberg, T. Biochemistry 1995 34 13594 13602There is no corresponding record for this reference.
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35Yli-Kauhaluoma, J. T., Ashley, J. A., Lo, C.-H. L., Coakley, J., Wirsching, P., and Janda, K. D. J. Am. Chem. Soc. 1996 118 5496 5497There is no corresponding record for this reference.
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36Zydowsky, L. D., Etzkorn, F. A., Chang, H. Y., Ferguson, S. B., Stolz, L. A., Ho, S. I., and Walsh, C. T. Protein Sci. 1992 1 1092 109936https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhs1Cisrc%253D&md5=a68ce94f777c5aec962caefc083d7b8cActive site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibitionZydowsky, Lynne D.; Etzkorn, Felicia A.; Chang, Howard Y.; Ferguson, Stephen B.; Stolz, Lesley A.; Ho, Susanna I.; Walsh, Christopher T.Protein Science (1992), 1 (9), 1092-9CODEN: PRCIEI; ISSN:0961-8368.Based on recent x-ray structural information, 6 site-directed mutants of human cyclophilin A (hCyPA) involving residues in the putative active site (His-54, Arg-55, Phe-60, Gln-111, Phe-113, and His-126) were constructed, overexpressed, and purified from Escherichia coli to homogeneity. Mutant proteins W121A, H54Q, R55A, F60A, Q111A, F113A, and H126Q were assayed for peptidylprolyl cis-trans-isomerase (PPIase) activity, their ability to bind the immunosuppressive drug, cyclosporin A (CsA), and phosphoprotein phosphatase 2B (calcineurin) inhibition in the presence of CsA. The results indicated that H54Q, Q111A, F113A, and W121A retained 3-15% of the catalytic efficiency (kcat/Km) of wild-type recombinant hCyPA. The remaining 3 mutants (R55A, F60A, and H126Q) each retained <1% of the wild-type catalytic efficiency, indicating the participation of these residues in PPIase catalysis. Each of the mutants bound to a CsA affinity matrix. Mutants R55A, F60A, F113A, and H126Q inhibited calcineurin in the presence of CsA, whereas W121A did not. Although CsA is a competitive inhibitor of PPIase activity, was able to complex with enzymically inactive cyclophilins and inhibit the phosphatase activity of calcineurin.
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37Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W., and Klein, M. L. J. Chem. Phys. 1983 79 926 93537https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXksF2htL4%253D&md5=a1161334e381746be8c9b15a5e56f704Comparison of simple potential functions for simulating liquid waterJorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.; Impey, Roger W.; Klein, Michael L.Journal of Chemical Physics (1983), 79 (2), 926-35CODEN: JCPSA6; ISSN:0021-9606.Classical Monte Carlo simulations were carried out for liq. H2O in the NPT ensemble at 25° and 1 atm using 6 of the simpler intermol. potential functions for the dimer. Comparisons were made with exptl. thermodn. and structural data including the neutron diffraction results of Thiessen and Narten (1982). The computed densities and potential energies agree with expt. except for the original Bernal-Fowler model, which yields an 18% overest. of the d. and poor structural results. The discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons were made for the self-diffusion coeffs. obtained from mol. dynamics simulations.
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38Case, D. A., Cheatham, T. E., III., Darden, T., Gohlke, H., Luo, R., Merz, K. M., Jr., Onufriev, A., Simmerling, C., Wang, B., and Woods, R. J. J. Comput. Chem. 2005 26 1668 8838https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1SlsbbM&md5=93be29ff894bab96c783d24e9886c7d0The amber biomolecular simulation programsCase, David A.; Cheatham, Thomas E., III; Darden, Tom; Gohlke, Holger; Luo, Ray; Merz, Kenneth M., Jr.; Onufriev, Alexey; Simmerling, Carlos; Wang, Bing; Woods, Robert J.Journal of Computational Chemistry (2005), 26 (16), 1668-1688CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)The authors describe the development, current features, and some directions for future development of the Amber package of computer programs. This package evolved from a program that was constructed in the late 1970s to do Assisted Model Building with Energy Refinement, and now contains a group of programs embodying a no. of powerful tools of modern computational chem., focused on mol. dynamics and free energy calcns. of proteins, nucleic acids, and carbohydrates.
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39Hornak, V., Abel, R., Okur, A., Strockbine, B., Roitberg, A., and Simmerling, C. Proteins 2006 65 712 25There is no corresponding record for this reference.
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40Ryckaert, J. P., Ciccotti, G., and Berendsen, H. J. C. J. Comput. Phys. 1977 23 327 34140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXktVGhsL4%253D&md5=b4aecddfde149117813a5ea4f5353ce2Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanesRyckaert, Jean Paul; Ciccotti, Giovanni; Berendsen, Herman J. C.Journal of Computational Physics (1977), 23 (3), 327-41CODEN: JCTPAH; ISSN:0021-9991.A numerical algorithm integrating the 3N Cartesian equation of motion of a system of N points subject to holonomic constraints is applied to mol. dynamics simulation of a liq. of 64 butane mols.
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41Shen, T., and Hamelberg, D. J. Chem. Phys. 2008 129034103There is no corresponding record for this reference.
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42Grubmuller, H. Phys. Rev. E.: Stat. Phys., Plasmas, Fluids, Relat. Interdiscip. Top. 1995 52 2893 2906There is no corresponding record for this reference.
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43Voter, A. F. Phys. Rev. Lett. 1997 78 3908 3911There is no corresponding record for this reference.
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44Gong, X. G., and Wilkins, J. W. Phys. Rev. B: Condens. Mater. Sci. 1999 59 54 5744https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXit1KgtQ%253D%253D&md5=bf7c2d0756452b91d7f49d653fc1792eHyper molecular dynamics with a local bias potentialGong, X. G.; Wilkins, J. W.Physical Review B: Condensed Matter and Materials Physics (1999), 59 (1), 54-57CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)We propose a local bias potential for hyper mol. dynamics requiring no pre-knowledge of the saddle points of system. This has little computational overload and is applicable to real systems. Speedups of one to five orders of magnitude are found in the diffusion of a small cluster on a surface.
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45Rahman, J. A., and Tully, J. C. J. Chem. Phys. 2002 116 8750 8760There is no corresponding record for this reference.
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46Steiner, M. M., Genilloud, P. A., and Wilkins, J. W. Phys. Rev. B: Condens. Mater. Sci. 1998 57 10236 1023946https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXisVGntr0%253D&md5=759a82c4f5b4ecff72c78861ec2bffe1Simple bias potential for boosting molecular dynamics with the hyperdynamics schemeSteiner, M. M.; Genilloud, P.-A.; Wilkins, J. W.Physical Review B: Condensed Matter and Materials Physics (1998), 57 (17), 10236-10239CODEN: PRBMDO; ISSN:0163-1829. (American Physical Society)Two modifications of Voter's hyperdynamics scheme offer significant speedup of mol. dynamics simulations. (1) A simple construction of the bias potential (a few tens of lines of code) is validated for three systems. (2) A local construction of the bias potential permits the use of intuition to further improve the statistical error. These results suggest widespread applicability and the possibility of overcoming the unfavorable exponential scaling of mol. dynamics simulations as the temp. is lowered.
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47Wang, J. C., Pal, S., and Fichthorn, K. A. Phys. Rev. B: Condens. Mater. Sci. 2001 6308 9There is no corresponding record for this reference.
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