Abstract：
:The d-Ala:d-Lac ligase, VanA, plays a critical role in the resistance of vancomycin. Indeed, it is involved in the synthesis of a peptidoglycan precursor, to which vancomycin cannot bind. The reaction catalyzed by VanA requires the opening of the so-called "ω-loop", so that the substrates can enter the active site. Here, the conformational landscape of VanA is explored by an enhanced sampling approach: the temperature-accelerated molecular dynamics (TAMD). Analysis of the molecular dynamics (MD) and TAMD trajectories recorded on VanA permits a graphical description of the structural and kinetics aspects of the conformational space of VanA, where the internal mobility and various opening modes of the ω-loop play a major role. The other important feature is the correlation of the ω-loop motion with the movements of the opposite domain, defined as containing the residues A149-Q208. Conformational and kinetic clusters have been determined and a path describing the ω-loop opening was extracted from these clusters. The determination of this opening path, as well as the relative importance of hydrogen bonds along the path, permit one to propose some key residue interactions for the kinetics of the ω-loop opening.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Duclert-Savatier N,Bouvier G,Nilges M,Malliavin TEdoi
10.1021/acs.jcim.6b00211subject
Has Abstractpub_date
2016-09-26 00:00:00pages
1762-75issue
9eissn
1549-9596issn
1549-960Xjournal_volume
56pub_type
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