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Exploring the Helix-Coil Transition via All-Atom Equilibrium Ensemble Simulations

Department of Chemistry, Stanford University, Stanford, California 94305-5080

Correspondence: Address reprint requests to Vijay S. Pande, Assistant Professor, Dept. of Chemistry, Structural Biology Department and Stanford Synchrotron Radiation Laboratory 85, Stanford University, Stanford, CA 94305-3080. Tel.: 650-723-3660; Fax: 650-725-0259; E-mail: pande{at}stanford.edu.

The ensemble folding of two 21-residue -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-99, which shows improved agreement with experimental kinetic and thermodynamic measurements. From bulk analysis of the simulated AMBER-99 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.

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