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Simulated dipeptide recognition by vancomycin
Author(s) -
Li Daohui,
Sreenivasan Uma,
Juranic Nenad,
Macura Slobodan,
Puga Francisco J.,
Frohnert Paul M.,
Axelsen Paul H.
Publication year - 1997
Publication title -
journal of molecular recognition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.401
H-Index - 79
eISSN - 1099-1352
pISSN - 0952-3499
DOI - 10.1002/(sici)1099-1352(199703/04)10:2<73::aid-jmr347>3.0.co;2-1
Subject(s) - dipeptide , chemistry , vancomycin , glycopeptide , intermolecular force , molecular dynamics , hydrogen bond , glycopeptide antibiotic , molecular recognition , antibiotics , stereochemistry , nuclear magnetic resonance spectroscopy , combinatorial chemistry , computational chemistry , molecule , peptide , biochemistry , bacteria , biology , organic chemistry , genetics , staphylococcus aureus
The antimicrobial activity of vancomycin and related glycopeptide antibiotics is due to stereospecific recognition of polypeptide components in bacterial cell walls. To better understand how these antibiotics recognize polypeptide determinants, we have developed dynamic models of the complexes formed by the vancomycin aglycon and two different dipeptide ligands, Ac‐D‐ala‐D‐ala and Ac‐D‐ala‐gly. Molecular dynamics simulations of the two complexes, initially conditioned with distance constraints derived from two‐dimensional nuclear magnetic resonance (NMR) studies, are conformationally stable and propagate in a manner consistent with the NMR‐derived constraints after the constraints are removed. Free energy calculations accurately predict the relative binding affinity of these two complexes and help validate the simulation models for detailed structural analysis. Although the two ligands adopt similar conformations when bound to the antibiotic, there are clear differences in the configuration of intermolecular hydrogen bonds, the overall shape of the antibiotic, and other structural features of the two complexes. This analysis illustrates how complex structural and dynamic factors interrelate and contribute to differences in binding affinity. © 1997 John Wiley & Sons, Ltd.