KINETICS OF PEPTIDE FOLDING - COMPUTER-SIMULATIONS OF SYPFDV AND PEPTIDE VARIANTS IN WATER

The folding of Ser-Tyr-Pro-Phe-Asp-Val (SYPFDV), and sequence variants of this peptide (SYPYD and SYPFD) are studied computationally in an e xplicit water environment. An atomically detailed model of the peptide is embedded in a sphere of TIP3P water molecules and its optimal stru cture is computed by simulated annealing. At distances from the peptid e that are beyond a few solvation shells, a continuum solvent model is employed. The simulations are performed using a mean field approach t hat enhances the efficiency of sampling peptide conformations. The com putations predict a small number of conformations as plausible folded structures. All have a type VI turn conformation for the peptide backb one, similar to that found using NMR. However, some of the structures differ from the experimentally proposed ones in the packing of the pro line ring with the aromatic residues. The second most populated struct ure has, in addition to a correctly folded backbone, the same hydropho bic packing as the conformation measured by NMR. Our simulations sugge st a kinetic mechanism that consists of three separate stages. The tim e-scales associated with these stages are distinct and depend differen tly on temperature. Electrostatic interactions play an initial role in guiding the peptide chain to a roughly correct structure as measured by the end-to-end distance. At the same time or later the backbone tor sions rearrange due to local tendency of the proline ring to form a tu rn: this step depends on solvation forces and is helped by loose hydro phobic interactions. In the final step, hydrophobic residues pack agai nst each other. We also show the existence of an off the pathway inter mediate, suggesting that even in the folding of a small peptide ''misf olded'' structures can form. The simulations clearly show that paralle l folding paths are involved. Our findings suggest that the process of peptide folding shares many of the features expected for the signific antly larger protein molecules. (C) 1997 Academic Press Limited.