THERMODYNAMICS OF A REVERSE TURN MOTIF - SOLVENT EFFECTS AND SIDE-CHAIN PACKING

The linear pentapeptide, Ala-Tyr-cis-Pro-Tyr-Asp-NMA (AYPYD) is known to have a significant population of type VI turn conformers in aqueous solvent. We have carried out theoretical studies of the conformationa l energetics of this peptide using a potential of mean force (PMF) con sisting of the AMBER/OPLS empirical potential energy function, a macro scopic electrostatic model of polar solvation, and a surface area-base d model of non-polar solvation. Conformers were taken from molecular d ynamics simulations reported elsewhere, or generated by a random searc h method reported here. The chain entropy of folding was calculated by a systematic search of accessible dihedral angle space. The intra-pep tide component was found to strongly favor folding and was nearly canc elled by the polar solvation term which disfavored folding. The non-po lar solvation term had Little effect. Fluctuations about the average v alue of the PMF were small and in accord with estimates from a simple harmonic model. When applied to conformers generated by a random searc h, the PMF selected a conformer close to the NMR-determined structure as the lowest energy conformer. The conformer with the second-lowest e nergy was extended, but was found to fold rapidly to the turn state in a subsequent molecular dynamics study, and may be an important state on the folding-unfolding pathway. Averages of the PMF were combined wi th the entropy estimates to provide an estimate of the free energy of folding that is in reasonable agreement with experimental results. Ln terms of the interplay between backbone electrostatic interactions and the packing of apolar side-chains, this peptide provides a model for the energetics of protein folding, and therefore makes a useful test c ase for calculations. (C) 1997 Academic Press Limited.