Solvation of the Boc-Val-Phe-nPr peptide characterized by VCD spectroscopy and DFT calculations

The conformational preferences of peptides are strongly determined by hydrogen bonding interactions. Intermolecular solute-solvent interactions compete with intramolecular interactions, which typically stabilize the secondary structure of the peptide. The analysis of vibrational circular dichroism (VCD) spectra can give insights into solvation-induced changes in the conformational distribution of small peptides. Here we describe the VCD spectroscopic characterization of the model peptide Boc-Val-Phe-nPr in chloroform as representative for a weakly interacting solvent and dimethyl sulfoxide (DMSO-d₆) as a strongly hydrogen bonding solvent. We show that the conformational preferences of the peptide in chloroform are well-described by the computationally predicted distribution of the isolated molecule assuming only implicit solvation effects through a continuum solvation model. In order to simulate the spectra recorded in DMSO-d₆, solvation was accounted for explicitly by computed microsolvated structures containing one to three solvent molecules. A good match of the computed spectra with the experimental data is obtained by this method. Comparing the conformational distributions in deuterated chloroform-d₁ and DMSO-d₆, structures with intramolecular hydrogen bonds such as the (δ,δ)-conformer family contribute to the conformational distribution only when there is no strong interaction with the solvent. This is in contrast to the results for the related Boc-Pro-Phe-nPr studied before, for which the intramolecular interaction was found to persist in DMSO-d₆. Furthermore, we discuss the influence of hydrogen bonding to different numbers of solvent molecules on the spectral signatures and show that the structure of the peptide in DMSO-d₆ is best described as a mixture of twofold-solvated (δ,β)- and threefold-solvated (β,β)-conformers.