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

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Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Building 240, Argonne, Illinois 60439, and Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, University of Chicago, 929 57th Street, Chicago, Illinois 60637
* Corresponding author e-mail: [email protected]
†Argonne National Laboratory.
‡University of Chicago.
Cite this: J. Chem. Theory Comput. 2010, 6, 9, 2559–2565
Publication Date (Web):July 30, 2010
https://doi.org/10.1021/ct1001768
Copyright © 2010 American Chemical Society

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    Abstract

    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 “λ” 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 λ 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 λ and the boosting potential, in an extended dual array of coupled λ- 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 λ-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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