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

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.

Quantum Mechanics Approach to Hydration Energies and Structures of Alanine and Dialanine

“…The data were analyzed by means of a two‐state model, and they asserted that at room temperature dialanine mainly populates the PPII conformation with a fraction of β‐like conformation, but as the temperature is increased the fraction of PPII structure decreases in favor of the β structure. Currently, this view seems to be the most accepted in the scientific community, since it is in line with studies on several other protected peptides and tripeptides …”

“…The data reported in Table clearly show that the β→PPII structural transformation is energetically favored (Δ E <0) for both cationic and zwitterionic dialanine. This stabilization is due to the better coordination of water molecules around the peptide in the PPII conformation, in analogy to what is seen for other tripeptides and protected alanine . The Δ E value computed with traditional ab initio methods undergoes minor variations on improving both the basis set and the treatment of electronic correlation, and values of −4.7±0.6 and −7.9±1.2.…”

“…Currently,t his view seems to be the mosta ccepted in the scientific community, since it is in line with studies on several otherp rotected peptidesa nd tripeptides. [37][38][39][64][65][66][67] Furthermore, by meanso fav an't Hoff plot, Schweitzer-Stenner et al derived accurate thermodynamic parameters (DH8 and DS8)f or the bÐPPIIe quilibrium of the cation. [45] Unfortunately,a tn eutral pH, the UVCD spectrumi sc omplicated by the presence of additional contributionsf rom the n!p*a nd p!p*c harge-transfer transitions from the C-terminal carboxylate to the peptideg roup, which do not permit ac omfortable quantitative analysis, and thus DH8 and DS8 data have not been reported.…”

“…This stabilization is due to the better coordination of water molecules around the peptidei nt he PPII conformation, in analogyt ow hat is seen for other tripeptides and protected alanine. [31][32][33][34]64] The DE value computed with traditional ab initio methods undergoes minor variations on improvingb oth the basis set and the treatment of electronicc orrelation, and values of À4.7 AE 0.6 and À7.9 AE 1.2. kcal mol À1 can be assumed as the best computational evaluation for cation and zwitterion, respectively.R elativet ot hese values, M06-2X predicts al ess exoenergeticv alue for the cation (À1.5 kcal mol À1 ), whereas the zwitterion is computed to be more exoenergetic( À8.8 kcal mol À1 ). The electronic-structure approacha nd in particular the methodu sed for electronic correlation evaluation is ak ey ele-ment in the "computational pot" oriented to ar eliable description of hydration phenomena in biomolecules.…”

Effect of the solvent on the conformational behavior of the alanine dipeptide deduced from MD simulations

“…show an increase population of the αR conformation in comparison to alanine dipeptide calculations [42,43].…”