title: Building Graphs To Describe Dynamics, Kinetics, and Energetics in the d-ALa:d-Lac Ligase VanA.
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.
authors: Département de Biologie Structurale et Chimie, Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3528 , 25, rue du Dr Roux, 75015 Paris, France.
authors: Nathalie
authors: N
authors: Duclert-Savatier
authors: Département de Biologie Structurale et Chimie, Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3528 , 25, rue du Dr Roux, 75015 Paris, France.
authors: Guillaume
authors: G
authors: Bouvier
authors: Département de Biologie Structurale et Chimie, Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3528 , 25, rue du Dr Roux, 75015 Paris, France.
authors: Michael
authors: M
authors: Nilges
authors: Département de Biologie Structurale et Chimie, Institut Pasteur, Unité de Bioinformatique Structurale, CNRS UMR 3528 , 25, rue du Dr Roux, 75015 Paris, France.
authors: Thérèse E
authors: TE
authors: Malliavin
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D019729:Carbon-Oxygen Ligases / Q000737:chemistry / Q000378:metabolism*; D003196:Computer Graphics; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013696:Temperature
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; C071437:VanA ligase, Bacteria; D019729:Carbon-Oxygen Ligases