Determination of the structures of distinct transition state ensembles for a β-sheet peptide with parallel folding pathways

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Abstract
The occurrence of well defined multiple folding pathways, although possible in principle, is rarely observed experimentally in small globular proteins. In molecular dynamics simulations, however, β3s, a synthetic 20 residue peptide, folds along two alternative pathways into a monomeric β-sheet structure. The structures of the corresponding transition states for folding have been defined in these simulations [Ferrara and Caflisch, PNAS 97, 10780 (2000)]. We describe a method for the simultaneous back-calculation of the two transition state structures of β3s from the knowledge of the average number of native contacts formed by individual residues. The structures are determined by a Monte Carlo approach in which two replicas of the peptide are simulated in parallel. This procedure generalizes one that we have recently developed to determine transition state structures from experimental φ values. Our results show that, while the short peptide β3s has two folding pathways, the 98 residue protein AcP folds via a single pathway. We conclude by discussing how evolution may have selected single folding pathways as a “quality control” mechanism to avoid misfolding.