title: Exploring the helix-coil transition via all-atom equilibrium ensemble simulations.
abstract: The ensemble folding of two 21-residue alpha-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 phi, which shows improved agreement with experimental kinetic and thermodynamic measurements. From bulk analysis of the simulated AMBER-99 phi 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.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorin
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D000465:Algorithms; D001703:Biophysics / Q000379:methods*; D016000:Cluster Analysis; D003198:Computer Simulation; D004058:Diffusion; D006358:Hot Temperature; D007700:Kinetics; D008390:Markov Chains; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012984:Software; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D010455:Peptides; D011108:Polymers; C011083:polyproline; C019529:polyalanine