Ronald M. Levy

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

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 binding, folding, 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 binding and folding 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] Andrec, M., A.K. Felts, E. Gallicchio, and R.M. Levy. Protein folding pathways from replica exchange simulations and a kinetic network model. Proceedings Natl. Acad. Sci. USA, 102, 6801-6806 (2005) 

[2] Zheng, W., M. Andrec, E. Gallicchio, and R.M. Levy. Simulating replica exchange simulations of protein folding with a kinetic network model. Proceedings Natl. Acad. Sci. USA, 104, 15340-15345 (2007) 

[3] Gallicchio, E., K. Paris, and R.M. Levy. AGBNP2 Implicit Solvent Model. J. Chem. Theory & Comp., 5, 2544-2564 (2009)

[4] 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

[5] 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, Article ASAP. (2011) doi.10.1021/jp1089596 

[6] Gallicchio, E., and R.M. Levy. Advances in all atom sampling methods for modeling protein-ligand binding affinities. Current Opinion in Structural Biology, in press 2011

Ronald M. Levy is Professor of Chemistry in the Department of Chemistry and Chemical Biology, and BioMaPS Institute for Quantitative Biology at Rutgers University. For more information, please visit: http://levygroup.rutgers.edu.