Dominant Chemical Interactions Governing the Folding Mechanism of Oligopeptides

Abstract

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.

Keywords: dihedral angle calculations; dominant chemical interactions; folding mechanisms; main mechanical forces.

Figure 1

Mechanical forces related to (A) chemical interactions of the chignolin (1uao) folding process; (B) chemical interactions of the Leu–enkephalin folding process; and (C) chemical interactions of the CCR5 ECL2 (2mzx) folding process.

Figure 2

Physical measures that rule the folding mechanism at the single-residue level of TRP190. (A,B) Comparison between threshold distances and partial dihedral angles. (C,D) Comparison between developed mechanical forces and the related potential energy. Abbreviations: ri = threshold distance, δφ° = partial dihedral angle, F = mechanical force, U = potential energy, HI = hydrophobic interaction, HB = H-bond, EITC = electrostatic interaction between the terminal charges, π–π = π–π interaction or pi stacking, W = Tryptophan, Y = Tyrosine, Q = Glutamine, F = Phenylalanine, K = Lysine, N = Asparagine.

Figure 3

(A) Superimposition of the calculated without energy minimization (green) and the experimental structure (blue) of chignolin; (B) superimposition of the calculated without energy minimization (green) and the experimental structure (blue) of Leu-enkephalin; (C) superimposition of the calculated without energy minimization (green) and the experimental structure (blue) of CCR5 ECL2; (D) superimposition of the calculated after energy minimization (green) and the experimental structure (blue) of chignolin; (E) superimposition of the calculated after energy minimization (green) and the experimental structure (blue) of Leu-enkephalin; and (F) superimposition of the calculated after energy minimization (green) and the experimental structure (blue) of CCR5 ECL2.

Figure 4

Per-residue internal contacts between the calculated/predicted structures (green) and the structures with the lowest RMSD during MD simulations (red). (A) Chignolin, (B) Leu-enkephalin and (C) CCR5 ECL2.