Influence of solvation on the helix-forming tendency of nonpolar amino acids

This paper presents a computational study on helix folding and unfolding of length 10 homopeptides composed of the nonpolar amino acids methionine, al anine, leucine, phenylalanine, isoleucine, valine and glycine. We apply a M onte Carlo Simulated Annealing (MCSA) framework to derive energetic paramet ers which allow to differentiate between ct-helix formers and helix breaker s within this group of peptides, and especially emphasize solvation effects , modeled via a continuum approximation, on folding pathways and respective or-helix stability. Computed differences in potential energies of random c oil and folded states clearly show methionine, alanine and leucine as helix formers, whereas phenylalanine, and in particular isoleucine, valine and g lycine may be considered as helix destabilizing. This finding is also refle cted by helix unfolding simulations, which indicate considerable helix stab ility for the first group of peptides, but enhanced unfolding for the latte r four. Solvation effects do certainly affect the putative helix formation pathways for the seven model peptides considered and the paper presents a d etailed analysis on correlations between changes in potential energy as wel l as changes in total solvation (which is also factorized into its contribu tions derived from hydrophobic and hydrophilic surface areas) in respective folding and unfolding pathways. Correlation analysis of MCSA runs under co-optimization of potential and so lvation energies shows that solvation, in particular during the early stage , counteracts the potential energy-driven folding process. Decreases and in creases of potential and solvation energies are inversely correlated. We in terpret these results as such that potential energy minima are frequently a ssociated with solvation energy maxima on the folding energy landscape, in particular at the early stage of folding. This on the one hand prevents fol ds from being trapped in local minima of potential energy. On the other han d this mechanism could decrease the total number of actually accessible poi nts on the folding energy landscape (which have to be characterized as a co -optimum of potential and solvation energy), which would better define the folding pathway towards the native structure. The correlation analysis show s that the helix formers methionine, alanine, and leucine have reached such a combined optimum of potential and solvation energy at the or-helical sta te, whereas helix destabilizing residues as isoleucine, valine and glycine unfold the helix, driven by a combination of both, potential energies and s olvation energy status. (C) 2000 Elsevier Science B.V. All rights reserved.