Helix nucleation kinetics from molecular simulations in explicit solvent

We study the reversible folding/unfolding of short Ala and Gly-based peptid es by molecular dynamics simulations of all-atom models in explicit water s olvent. A kinetic analysis shows that the formation of a first or-helical t urn occurs within 0.1-1 ns, in agreement with the analyses of laser tempera ture jump experiments. The unfolding times exhibit Arrhenius temperature de pendence. For a rapidly nucleating all-Ala peptide, the helix nucleation ti me depends only weakly on temperature. For a peptide with enthalpically com peting turn-like structures, helix nucleation exhibits an Arrhenius tempera ture dependence, corresponding to the unfolding of enthalpic traps in the c oil ensemble. An analysis of structures in a "transition-state ensemble" sh ows that helix-to-coil transitions occur predominantly through breaking of hydrogen bonds at the helix ends, particularly at the C-terminus. The tempe rature dependence of the transition-state ensemble and the corresponding fo lding/unfolding pathways illustrate that folding mechanisms can change with temperature, possibly complicating the interpretation of high-temperature unfolding simulations. The timescale of helix formation is an essential fac tor in molecular models of protein folding. The rapid helix nucleation obse rved here suggests that transient helices form early in the folding event. Proteins 2001;42:77-84. (C) 2000 Wiley-Liss, Inc.