Folding simulations of a three-stranded antiparallel beta-sheet peptide

Protein folding is a grand challenge of the postgenomic era. In this paper, 58 folding events sampled during 47 molecular dynamics trajectories for a total simulation time of more than 4 mu s provide an atomic detail picture of the folding of a 20-residue synthetic peptide with a stable three-strand ed antiparallel beta-sheet fold. The simulations successfully reproduce the NMR solution conformation, irrespective of the starting structure. The sam pling of the conformational space is sufficient to determine the free energ y surface and localize the minima and transition states. The statistically predominant folding pathway involves the formation of contacts between stra nds 2 and 3. starting with the side chains close to the turn, followed by a ssociation of the N-terminal strand onto the preformed 2-3 beta-hairpin. Th e folding mechanism presented here, formation of a beta-hairpin followed by consolidation, is in agreement with a computational study of the free ener gy surface of another synthetic three-stranded antiparallel beta-sheet by B ursulaya and Brooks [(1999) J. Am. Chem. Soc. 121. 9947-9951]. Hence, it mi ght hold in general for antiparallel beta-sheets with short turns.