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

Abstract

This paper presents a computational study on helix folding and unfolding of length 10 homopeptides composed of the nonpolar amino acids methionine, alanine, leucine, phenylalanine, isoleucine, valine and glycine. We apply a Monte Carlo Simulated Annealing (MCSA) framework to derive energetic parameters which allow to differentiate between α-helix formers and helix breakers within this group of peptides, and especially emphasize solvation effects, modeled via a continuum approximation, on folding pathways and respective α-helix stability. Computed differences in potential energies of random coil and folded states clearly show methionine, alanine and leucine as helix formers, whereas phenylalanine, and in particular isoleucine, valine and glycine may be considered as helix destabilizing. This finding is also reflected by helix unfolding simulations, which indicate considerable helix stability for the first group of peptides, but enhanced unfolding for the latter four.Solvation effects do certainly affect the putative helix formation pathways for the seven model peptides considered and the paper presents a detailed analysis on correlations between changes in potential energy as well as changes in total solvation (which is also factorized into its contributions derived from hydrophobic and hydrophilic surface areas) in respective folding and unfolding pathways.Correlation analysis of MCSA runs under co-optimization of potential and solvation energies shows that solvation, in particular during the early stage, counteracts the potential energy-driven folding process. Decreases and increases of potential and solvation energies are inversely correlated. We interpret these results as such that potential energy minima are frequently associated with solvation energy maxima on the folding energy landscape, in particular at the early stage of folding. This on the one hand prevents folds from being trapped in local minima of potential energy. On the other hand this mechanism could decrease the total number of actually accessible points 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 shows that the helix formers methionine, alanine, and leucine have reached such a combined optimum of potential and solvation energy at the α-helical state, whereas helix destabilizing residues as isoleucine, valine and glycine unfold the helix, driven by a combination of both, potential energies and solvation energy status.