MOLECULAR-DYNAMICS SIMULATIONS OF SYNTHETIC PEPTIDE FOLDING

Because the time scale of protein folding is much greater than that of the widely used simulations of native structures, a detailed report o f molecular dynamics simulations of folding has not been available, In this study, we included the average solvent effect in the potential f unctions to simplify the calculation of the solvent effect and carried out long molecular dynamics simulations of the alanine-based syntheti c peptides at 274 K. From either an extended or a randomly generated c onformation, the simulations approached a helix-coil equilibrium in ab out 3 ns. The multiple minima problem did not prevent helix folding, T he calculated helical ratio of Ac-AAQ-AAAAQAAAAQAAY-NH2 was 47%, in go od agreement with the circular dichroism measurement (about 50%). A he lical segment with frayed ends was the most stable conformation, but t he hydrophobic interaction favored the compact, distorted helix-turn-h elix conformations. The transition between the two types of conformati ons occurred in a much larger time scale than helix propagation. The t ransient hydrogen bonds between the glutamine side chain and the backb one carbonyl group could reduce the free energy barrier of helix foldi ng and unfolding. The substitution of a single alanine residue in the middle of the peptide with valine or glycine decreased the average hel ical ratio significantly, in agreement with experimental observations. (C) 1996 Wiley-Liss, Inc.