Atomic-resolution dissection of the energetics and mechanism of isomerization of hydrated ATP-Mg(2+) through the SOMA string method

J Comput Chem. 2016 Mar 5;37(6):575-86. doi: 10.1002/jcc.23991. Epub 2015 Jul 7.


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.

Keywords: free-energy calculations; metadynamics; molecular dynamics simulations; replica-exchange; string method.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Isomerism
  • Molecular Dynamics Simulation
  • Thermodynamics
  • Water / chemistry*


  • Water
  • Adenosine Triphosphate