Side chain interactions govern the response of polypeptide alpha-helices under mechanical stress and prevent the formation of beta-sheets

Abstract

Secondary a-helix and b-sheet structures are key scaffolds around which the rest of the residues condense during protein folding. They are crucial for proteins to adopt their correct native structure. Despite their key role in numerous processes to maintain life, little is known about their properties under force. Their stability under mechanical stress, as constantly experienced in the turbulent environment of cells, is however essential. Here, we designed and synthesized two pH-responsive polypeptides, poly(L-glutamic acid) and poly(L-lysine), for optimal interfacing with an AFM single-molecule force spectroscopy set-up to probe the mechanical unfolding of a-helix and b-sheet secondary motifs. The force experiments, supported by simulations, reveal a superior mechanical stability of the poly(L-Lysine) a-helix, which we attribute to hydrophobic interactions of the alkyl side chains. Most importantly, our results show that these interactions play a key role in inhibiting the formation of a metastable b-sheet-like structure when the polypeptide is subjected to mechanical deformations, which might have important implications in the mechanism behind polyQ diseases.

Recent advances in the solution self‐assembly of polypeptides

“…34,35 The key structural difference between these helix forms is a slight variation in the stretching degree of the polypeptide backbone, which can be induced by stimuli such as external force. 36 The variation of the stretching degree of the polypeptide helix has been found to alter the morphology of the assembly. In a recent work, He et al discovered that the PBLG 100 is hydrated at low water contents and adopts an α-helix conformation.…”