Assessing backbone solvation effects in the conformational propensities of amino acid residues in unfolded peptides

Conformational ensembles of individual amino acid residues within model GxG peptides (x representing different amino acid residues) are dominated by a mixture of polyproline II (pPII) and β-strand like conformations. We recently discovered rather substantial differences between the enthalpic and entropic contributions to this equilibrium for different amino acid residues. Isoleucine and valine exceed all other amino acid residues in terms of their rather large enthalpic stabilization and entropic destabilization of polyproline II. In order to shed light on these underlying physical mechanisms, we performed high-level DFT calculations to explore the energetics of four representative GxG peptides where x = alanine (A), leucine (L), valine (V), and isoleucine (I) in explicit water (10 H2O molecules with a polarizable continuum water model) and in vacuo. We found that the large energetic contributions to the stabilization of pPII result, to a major extent, from peptide–water, water–water interactions, and changes of the solvent self-energy. Differences between the peptide–solvent interaction energies of hydration in pPII and β-strand peptides are particularly important for the pPII ⇌ β equilibria of the more aliphatic peptides GIG and GLG. Furthermore, we performed a vibrational analysis of the four peptides in both conformations and discovered a rather substantial mixing between water motions and peptide vibrations below 700 cm−1. We found that the respective vibrational entropies are substantially different for the considered conformations, and their contributions to the Gibbs/Helmholtz energy stabilize β-strand conformations. Taken together, our results underscore the notion of the solvent being the predominant determinant of peptide (and protein) conformations in the unfolded state.