Computation of Absolute Hydration and Binding Free Energy with Free Energy Perturbation Distributed Replica-Exchange Molecular Dynamics

Distributed Replica (REPDSTR) is a powerful parallelization technique enabling simulations of a group of replicas in a parallel/parallel fashion, where each replica is distributed to different nodes of a large cluster [Theor. Chem. Acc. 2003, 109,140]. Here, we use the framework provided by REPDSTR to combine a staged free energy perturbation protocol with replica-exchange molecular dynamics (FEP/REMD). The structure of REPDSTR, which allows multiple parallel input/output (I/O), facilitates the treatment of replica-exchange to couple the N window simulations corresponding to different values of the thermodynamic coupling parameters. As a result, each of the N synchronous window simulations benefit from the sampling carried out by the N-1 others. As illustrative examples of the FEP/REMD strategy, calculations of the absolute hydration and binding free energy of small molecules were performed using the biomolecular simulation program CHARMM adapted for the IBM Blue Gene/P platform. The computations show that a FEP/REMD strategy significantly improves the sampling and accelerates the convergence of absolute free energy computations.