Protein Folding Landscapes for Alpha- and Beta-Miniproteins Using All-Atom Simulations with an Optimized Force-Field

Abstract

With recent advances in simulation methodology and computer hardware, it has become possible to access physical phenomena occurring on the microsecond timescale with molecular dynamics simulations. Even though most naturally occurring proteins fold on a much slower timescale (milliseconds to seconds), the design of miniproteins (e.g., trpcage, trpzip, beta-hairpin) and proteins (e.g., Villin) which fold close to the protein folding-speed limit (∼ 1 μs) have made feasible direct, high resolution, simulations of protein folding. At the same time, the shortcomings in the current energy functions for proteins are becoming increasingly evident with clear biases in secondary structure preference of different force fields being reflected in which proteins they are able to fold. To be able to compare and complement experimental observations, an ideal force-field would be able to fold different types of secondary structure without additional modifications or inputs.We will present results from extensive replica exchange molecular dynamics simulations for folding of GB1 beta-hairpin and trpcage (representing beta and alpha structures respectively) with a force field based on AMBER ff03 and optimized only to reproduce the helix-coil transition. We obtain converged equilibrium distributions for runs starting from a completely unfolded state and from the native state, with folded populations at room temperature in quantitative agreement with experiment. The folded structures for both the proteins (starting from a completely unfolded structure) have average backbone dRMS from the experimental structures of less than 1 A. Finally, we will present results for the 35-residue protein Villin. Although convergence of equilibrium distributions in this case is not computationally feasible, we nonetheless obtain a folded structure within 1 A dRMS of the native structure, starting from a completely unfolded coil-like conformation.