Secondary Forces in Protein Folding

Abstract

A complete inventory of the forces governing protein folding is critical for productive protein modeling, including structure prediction and de novo design, as well as understanding protein misfolding diseases of clinical significance. The dominant contributors to protein folding include the hydrophobic effect and conventional hydrogen bonding, along with Coulombic and van der Waals interactions. Over the past few decades, important additional contributors have been identified, including C-H···O hydrogen bonding, n→π* interactions, C5 hydrogen bonding, chalcogen bonding, and interactions involving aromatic rings (cation-π, X-H···π, π-π, anion-π, and sulfur-arene). These secondary contributions fall into two general classes: (1) weak but abundant interactions of the protein main chain and (2) strong but less frequent interactions involving protein side chains. Though interactions with high individual energies play important roles in specifying nonlocal molecular contacts and ligand binding, we estimate that weak but abundant interactions are likely to make greater overall contributions to protein folding, particularly at the level of secondary structure. Further research is likely to illuminate additional roles of these noncanonical interactions and could also reveal contributions yet unknown.

Figure 1.

Secondary interactions involving the main chain. (A) Structural model of an idealized β-sheet, showing conventional main-chain hydrogen bonds (black dashes), C–H···O hydrogen bonds (green dashes), and C5 hydrogen bonds (blue dashes). (B) Structural model of an idealized α-helix, showing main-chain hydrogen bonds (black dashes) and n→π* interactions (blue arrows). (C,D) Orbital overlap that underlies formation of n→π* interactions (C) and C5 hydrogen bonds (D).

Figure 2.

Secondary interactions involving side chains.

Figure 3.

Bar graph of the estimated enthalpic contribution of secondary interactions to the conformational stability of globular proteins. Black bars, interactions of the main chain (Figure 1); gray bars, interactions involving side chains (Figure 2). Data are from Table 1. The sum of the energies is ~27 kcal/mol per 100 residues.