We report atomically detailed molecular dynamics (MD) simulations of protein-peptide binding events with rigorous kinetics. The system is a classic protein-peptide complex involving the MDM2 oncoprotein and an intrinsically disordered peptide fragment of tumor suppressor p53. Due to the long timescales required, the simulation of protein binding events is currently not feasible with �brute force� MD simulations on typical computing resources. By applying the �weighted ensemble� path sampling approach in conjunction with MD simulations, we obtained more than 1100 continuous pathways of MDM2-p53 peptide binding events with a computed association rate constant that is the same order of magnitude as the experimentally measured value. We obtained these pathways within 20 days on the NSF-funded XSEDE Ranger supercomputer, using our parallel implementation of the weighted ensemble approach that has been optimized for large core-count supercomputers. Results provide direct views of protein-peptide binding events at an unprecedented level of detail.

Efficient molecular dynamics simulations of protein-peptide binding kinetics

244th National Meeting (2012)

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