4.7 Article

Free Energy Perturbation Hamiltonian Replica-Exchange Molecular Dynamics (FEP/H-REMD) for Absolute Ligand Binding Free Energy Calculations

Journal

JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 6, Issue 9, Pages 2559-2565

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/ct1001768

Keywords

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Funding

  1. National Science Foundation [MCB-0920261]
  2. Office of Science of the U.S. Department of Energy (DOE) [DE-AC02-06CH11357]
  3. U.S. DOE Office of Science laboratory [DE-AC02-06CH11357]
  4. DOE
  5. Div Of Molecular and Cellular Bioscience
  6. Direct For Biological Sciences [920261] Funding Source: National Science Foundation

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Free Energy Perturbation with Replica Exchange Molecular Dynamics (FEP/REMD) offers a powerful strategy to improve the convergence of free energy computations. In particular, it has been shown previously that a FEP/REMD scheme allowing random moves within an extended replica ensemble of thermodynamic coupling parameters lambda can improve the statistical convergence in calculations of absolute binding free energy of ligands to proteins [J. Chem. Theory Comput. 2009, 5, 2583]. In the present study, FEP/REMD is extended and combined with an accelerated MD simulations method based on Hamiltonian replica-exchange MD (H-REMD) to overcome the additional problems arising from the existence of kinetically trapped conformations within the protein receptor. In the combined strategy, each system with a given thermodynamic coupling factor lambda in the extended ensemble is further coupled with a set of replicas evolving on a biased energy surface with boosting potentials used to accelerate the interconversion among different rotameric states of the side chains in the neighborhood of the binding site. Exchanges are allowed to occur alternatively along the axes corresponding to the thermodynamic coupling parameter lambda and the boosting potential, in an extended dual array of coupled lambda- and H-REMD simulations. The method is implemented on the basis of new extensions to the REPDSTR module of the biomolecular simulation program CHARMM. As an illustrative example, the absolute binding free energy of p-xylene to the nonpolar cavity of the L99A mutant of the T4 lysozyme was calculated. The tests demonstrate that the dual lambda-REMD and H-REMD simulation scheme greatly accelerates the configurational sampling of the rotameric states of the side chains around the binding pocket, thereby improving the convergence of the FEP computations.

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