Past Event: Oden Institute Seminar

Exploring landscapes for protein folding, binding, and fitness using replica exchange and network models

Ronald Levy, Department of Chemistry and Chemical Biology, Rutgers University

Abstract

Advances in computational biophysics depend 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 several years concerning the construction of all-atom effective potentials for proteins and multi-scale methods for simulating their folding, binding, and fitness. The Analytical Generalized Born plus Non-Polar (AGBNP) model is an analytical implicit solvent model with origins in solution physical chemistry that is suitable for modeling solvated peptides, proteins, and small molecule solutes [1]. It is based on an analytical pairwise descreening implementation of the continuum dielectric Generalized Born model and a novel non-polar hydration free energy estimator. Since its introduction in 2004 AGBNP has been used to study a variety of problems in protein structural biology, including: peptide folding [2], protein allostery [3] and vaccine design [4]. I will describe the latest features of the AGBNP model which now includes the adoption of a molecular surface description of the solute volume, and the modeling of high occupancy hydration sites [5]. Replica exchange (RE) is a generalized ensemble 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 [6,7]. I will discuss new multi-scale approaches to recover protein folding rates using the combined power of replica exchange, a kinetic network model and effective stochastic dynamics [8]. Finally, I will describe recent work in the lab where we are beginning to explore the biophysical basis for the stability and fitness landscapes for proteins and their links to molecular evolution, focusing on the role of electrostatics. References [1] Gallicchio, E., and R.M. Levy. AGBNP, an Analytic Implicit Solvent Model Suitable for Molecular Dynamics Simulations and High-Resolution Modeling. J. Comp. Chem., 25, 479-499 (2004). [2] 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) [3] Ravindranathan, K.P., E. Gallicchio, R.A. Friesner, A.E. McDermott, and R.M. Levy. Conformational Equilibrium of Cytochrome P450 BM-3 Complexed with N-Palmitoylglycine: A Replica Exchange Molecular Dynamics Study. J. Am. Chem. Soc., 128, 3786-3791 (2006) [4] Lapelosa, M., E. Gallicchio, G. Ferstandig-Arnold, R.M. Levy, and E. Arnold. In silico vaccine design based on molecular simulations of rhinovirus chimeras presenting HIV-1 gp41 epitopes, J. Mol. Biol., 385, 675-691(2009) [5] Gallicchio, E., K. Paris, and R.M. Levy. The AGBNP2 Implicit Solvent Model. JCTC, in press (2009) [6] 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) [7] Zheng, W., M. Andrec, E. Gallicchio, and R.M. Levy. Simple continuous and discrete models for simulating replica exchange simulations of protein folding. J. Phys. Chem B., 112, 6083-6093 (2008) [8] Zheng, W., M. Andrec, E. Gallicchio, and R.M. Levy. Recovering Kinetics from a Simplified Protein-Folding Model using Replica Exchange Simulations, a Kinetic Network, and Effective Stochastic Dynamics, J. Phys. Chem B., 113, 11702-11709 (2009) [9] Haq, O., R.M. Levy, A. Morozov, and M. Andrec. Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease, BMC Bioinformatics, in press (2009) *Refreshments at 2:15