Exploring the Helix-Coil Transition via All-atom Equilibrium Ensemble Simulations.

Eric J. Sorin and Vijay S. Pande. Biophysical Journal (2005)

SUMMARY: How good are our models for folding? This question is important to address in order to understand the usefulness of our work, as well as the work of everyone in the atomistic simulation field in general. Here, we’ve done extremely extensive tests of models used in folding to show their strengths and weaknesses. Based on their weaknesses, we have proposed a new model which appears to have a much stronger agreement with experiment.

TECHNICAL ABSTRACT: The ensemble folding of two 21-residue a-helical peptides has been studied using all-atom simulations under several variants of the AMBER potential in explicit solvent using a global distributed computing network. Our extensive sampling, orders of magnitude greater than the experimental folding time, results in complete convergence to ensemble equilibrium. This allows for a quantitative assessment of these potentials, including a new variant of the AMBER-99 force field, denoted AMBER-99f, which shows improved agreement with experimental kinetic and thermodynamic measurements. From bulk analysis of the simulated AMBER-99f equilibrium, we find that the folding landscape is pseudo-two-state, with complexity arising from the broad, shallow character of the ‘native’ and ‘unfolded’ regions of the phase space. Each of these macrostates allows for configurational diffusion among a diverse ensemble of conformational microstates with greatly varying helical content and molecular size. Indeed, the observed structural dynamics are better represented as a conformational diffusion than as a simple exponential process, and equilibrium transition rates spanning several orders of magnitude are reported. After multiple nucleation steps, on average, helix formation proceeds via a kinetic “alignment” phase in which two or more short, low-entropy helical segments form a more ideal, single-helix structure.