Abstract
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.
Highlights
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 and b-strand like conformations
A recent conformational analysis of GxG peptides in water based on vibrational spectroscopic and NMR data revealed that most residues do predominantly sample the upper left quadrant of the Ramachandran plot, which can be subdivided into two sub-conformational ensembles associated with the b-strand and less extended polyproline II conformations.[12,15,16]
Individual amino acid residues differ in terms of the equilibrium between these two conformations – while alanine shows a clear preference for polyproline II (pPII), b-strand like conformations are slightly more preferred for valine and isoleucine
Summary
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 b-strand like conformations. DFT-based study by Lanza and Chiacchio on N-acetyl-L-alanine amide complexes with up to 13 water molecules revealed the existence of water clusters that were hydrogen bonded to the functional groups of the peptide backbone (i.e. CO and NH) They concluded that pPII conformations exhibit an energetic preference that leads to a greater reduction of water mobility,[32] further suggesting that pPII is energetically favored and entropically disfavored, in agreement with experimental data.[31] A more recent study by these authors confirmed this view in which the number of water molecules in the hydration shell was substantially increased up to 37.33 A somewhat lower number of water molecules (22) was found to be necessary for obtaining stabilization energies of pPII relative to the b-strand that are comparable with experimentally obtained values
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