Scrutiny of electrostatic-driven conformational ordering of polypeptide chains in DMSO: a study with a model oligopeptide

The physicochemical effects of the solvent DMSO on protein confirmation remain enigmatic despite its diverse applications in the proteomics field. Many attempts to understand the effects of DMSO have focused on the unfolding of α-helical-rich proteins; however, the cause of the profound stability of β-sheets in DMSO remains to be elucidated. Therefore, we designed an octapeptide as a β-hairpin fold to serve as a model β-sheet; we then performed combined experimental and simulation studies to investigate the effects of DMSO on the structure and stability of the β-hairpin. We compared the results of the designed octapeptide with its cognate polyalanine model to directly analyze the side chain interactions responsible for ordering the octapeptide in a specific conformation. NMR and simulation results established the ordering of the octapeptide as a β-hairpin fold, while simulations manifested the unfolded conformation of the cognate polyalanine in DMSO. It appears that owing to their weaker dielectric and strong dipolar strengths, DMSO abolishes the α-conformation as well as the solvated backbone amidic NH groups through hydrogen bonds; therefore, it destabilizes the intramolecular backbone hydrogen bonds, which leads to the unfolding of polyalanine peptides. Furthermore, our results conform to the possibility that DMSO stabilizes electrostatic and quadrupolar interactions among polar side chain atoms due to its low dielectric strength. Accordingly, we propose that the molecular mechanism of DMSO-induced stabilization of β-sheets is a combination of polar electrostatic interactions among the side chains and backbone desolvation through bulky side chains, which promotes backbone hydrogen bonding.