Advances in computational biophysics depend critically on the development of accurate effective potentials and powerful sampling methods to traverse the rugged energy landscapes that govern protein folding, binding and fitness. I will review work in my lab over the last few years concerning the construction of all-atom effective potentials for proteins and multi-scale methods for simulating their folding and binding on long time scales. Replica exchange (RE) is a generalized ensemble molecular simulation method for accelerating the exploration of free-energy landscapes which define many challenging problems in computational biophysics, including protein folding and binding. We have clarified some of the obstacles to obtaining converged thermodynamic information from RE simulations. I will discuss these issues and new multi-scale approaches to recover protein folding rates and pathways for folding and binding using the combined power of replica exchange, kinetic network models with flux analysis, and effective stochastic dynamics.References[1] Zheng, W., E. Gallicchio, N. Deng, M. Andrec, and R.M. Levy. Kinetic network study of the diversity and temperature Dependence of TRP-Cage Folding Pathways: Combining Transition Path Theory with Stochastic Simulations. J. Phys. Chem. B, 115, 1512-1523 (2011) doi.10.1021/jp1089596[2] Deng, N., W. Zheng, E. Gallicchio, and R.M. Levy. Insights into the Dynamics of HIV-1 Protease: a Kinetic Network Model Constructed from Atomistic Simulations, J. Am. Chem. Soc., 133, 9387-9394 (2011) doi.10.1021/ja2008032[3] Gallicchio, E., M. Lapelosa, and R.M.Levy. Binding Energy Distribution Analysis Method (BEDAM) for Estimation of Protein-Ligand Binding Affinities. J. Chem. Theory & Comp. 6, 2961-2977 (2010) doi.10.1021/ct1002913[4] Gallicchio, E., and R.M. Levy. Advances in all atom sampling methods for modeling protein-ligand binding affinities. Current Opinion in Structural Biology, 21, 161-166 (2011) doi.10.1016/j.sbi.2011.01.010Email: ronlevy@lutece.rutgers.eduWeb: http://levygroup.rutgers.edu

Exploring landscapes for protein folding and binding using replica exchange dynamics, kinetic networks and Markov state models

243rd National Meeting (2012)

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