beta-hairpin folding simulations in atomistic detail using an implicit solvent model

We have used distributed computing techniques and a supercluster of thousan ds of computer processors to study folding of the C-terminal beta -hairpin from protein G in atomistic detail using the GB/SA implicit solvent model a t 300 K. We have simulated a total of nearly 38 mus of, folding time and ob tained eight complete and independent folding trajectories. Starting from a n extended state, we observe relaxation to an unfolded state characterized by non-specific, temporary hydrogen bonding. This is followed by the appear ance of interactions between hydrophobic residues that stabilize a bent int ermediate. Final formation of the complete hydrophobic core occurs cooperat ively at the same time that the final hydrogen bonding pattern appears. The folded hairpin structures we observe all contain a closely packed hydropho bic core and proper beta -sheet backbone dihedral angles, but they differ i n backbone hydrogen bonding pattern. We show that this is consistent with t he existing experimental data on the hairpin alone in solution. Our analysi s also reveals short-lived semi-helical intermediates which define a thermo dynamic trap. Our results are consistent with a three-state mechanism with a single rate-limiting step in which a varying final hydrogen bond pattern is apparent, and senmi-helical off-pathway intermediates may appear early i n the folding process. We include details of the ensemble dynamics methodol ogy and a discussion of our achievements using this new computational devic e for studying dynamics at the atomic level. (C) 2001 Academic Press.