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

Abstract

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.