Dominant Chemical Interactions Governing the Folding Mechanism of Oligopeptides

The hydrophobic effect is the main factor that drives the folding of polypeptide chains. In this study, we have examined the influence of the hydrophobic effect in the context of the main mechanical forces approach, mainly in relation to the establishment of specific interplays, such as hydrophobic and CH–π cloud interactions. By adopting three oligopeptides as model systems to assess folding features, we demonstrate herein that these finely tuned interactions dominate over electrostatic interactions, including H-bonds and electrostatic attractions/repulsions. The folding mechanism analysed here demonstrates cooperation at the single-residue level, for which we propose the terminology of “single residues cooperative folding”. Overall, hydrophobic and CH–π cloud interactions produce the main output of the hydrophobic effect and govern the folding mechanism, as demonstrated in this study with small polypeptide chains, which in turn represent the main secondary structures in proteins.