title: Atomic-resolution dissection of the energetics and mechanism of isomerization of hydrated ATP-Mg(2+) through the SOMA string method.
abstract: The atomic mechanisms of isomerization of ATP-Mg(2+) in solution are characterized using the recently developed String Method with Optimal Molecular Alignment (SOMA) and molecular-dynamics simulations. Bias-Exchange Metadynamics simulations are first performed to identify the primary conformers of the ATP-Mg(2+) complex and their connectivity. SOMA is then used to elucidate the minimum free-energy path (MFEP) for each transition, in a 48-dimensional space. Analysis of the per-atom contributions to the global free-energy profiles reveals that the mechanism of these transitions is controlled by the Mg(2+) ion and its coordinating oxygen atoms in the triphosphate moiety, as well as by the ion-hydration shell. Metadynamics simulations in path collective variables based on the MFEP demonstrate these isomerizations proceed across a narrow channel of configurational space, thus validating the premise underlying SOMA. This study provides a roadmap for the examination of conformational changes in biomolecules, based on complementary enhanced-sampling techniques with different strengths. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Theoretical Molecular Biophysics Group, Max Planck Institute of Biophysics, Max-von-Laue Strasse 3, Frankfurt-am-Main, DE 60438, Germany.
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Building 5635FL, Suite T-800, Bethesda, Maryland, 20892.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marinelli
authors.affiliation: Theoretical Molecular Biophysics Group, Max Planck Institute of Biophysics, Max-von-Laue Strasse 3, Frankfurt-am-Main, DE 60438, Germany.|Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health, Building 5635FL, Suite T-800, Bethesda, Maryland, 20892.
authors.forename: José D
authors.initials: JD
authors.lastname: Faraldo-Gómez
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D014867:Water; D000255:Adenosine Triphosphate
keywords: free-energy calculations; metadynamics; molecular dynamics simulations; replica-exchange; string method