Secondary Forces in Protein Folding

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 tha...