We present results of a study to identify drug binding locations using GPU-accelerated Hamiltonian replica exchange molecular dynamics simulations. We use only a flat-bottom potential to restrain the ligand in the vicinity of the protein and let the ligand sample all available conformational space by applying a variety of Hamiltonian exchange and other sampling techniques to escape local minima. Replicas of fully interacting systems are coupled with less strongly interacting systems, molecular dynamics are GPU accelerated with the OpenMM toolkit, and Monte Carlo moves are added to improve sampling.  Because of the rigorous nature of the statistical mechanical sampling, we can also extract binding free energy estimates at all putative binding sites.  We develop the methodology on the T4 lysozyme model system, including rigorous convergence measures from independent starting configurations, and present results of the method on the 85 system Astex Diverse Set.

Identifying drug binding locations and poses using Hamiltonian replica exchange molecular dynamics

244th National Meeting (2012)

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