Time-Resolved Atomistic Imaging and Statistical Analysis of Daptomycin Oligomers with and without Calcium Ions
- Takayuki Nakamuro*
Takayuki Nakamuro*Email: [email protected]Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Takayuki Nakamuro
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- Ko Kamei
Ko KameiDepartment of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Ko Kamei
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- Keyi Sun
Keyi SunDepartment of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Keyi Sun
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- Jeffrey W. Bode
Jeffrey W. BodeLaboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich 8093, SwitzerlandMore by Jeffrey W. Bode
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- Koji Harano
Koji HaranoDepartment of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Koji Harano
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- Eiichi Nakamura*
Eiichi Nakamura*Email: [email protected]Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, JapanMore by Eiichi Nakamura
Abstract
Daptomycin (DP) is effective against multiple drug-resistant Gram-positive pathogens because of its distinct mechanism of action. An accepted mechanism includes Ca2+-triggered aggregation of the DP molecule to form oligomers. DP and its oligomers have so far defied structural analysis at a molecular level. We studied the ability of DP molecule to aggregate by itself in water, the effects of Ca2+ ions to promote the aggregation, and the connectivity of the DP molecules in the oligomers by the combined use of dynamic light scattering in water and atomic-resolution cinematographic imaging of DP molecules captured on a carbon nanotube on which the DP molecule is installed as a fishhook. We found that the DP molecule aggregates weakly into dimers, trimers, and tetramers in water, and strongly in the presence of calcium ions, and that the tetramer is the largest oligomer in homogeneous aqueous solution. The dimer remains as the major species, and we propose a face-to-face stacked structure based on dynamic imaging using millisecond and angstrom resolution transmission electron microscopy. The tetramer in its cyclic form is the largest oligomer observed, while the trimer forms in its linear form. The study has shown that the DP molecule has an intrinsic property of forming tetramers in water, which is enhanced by the presence of calcium ions. Such experimental structural information will serve as a platform for future drug design. The data also illustrate the utility of cinematographic recording for the study of self-organization processes.
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This article is cited by 2 publications.
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