UC Santa Barbara

The argument that the hydrophobic effect is the primary effect driving the folding of globular proteins is nearly universally accepted (including by the authors). But does this view also imply that water is a "poor" solvent for the unfolded states of these same proteins? Here we argue that the answer is "no," that is, folding to a well-packed, extensively hydrogen-bonded native structure differs fundamentally from the nonspecific chain collapse that defines a poor solvent. Thus, the observation that a protein folds in water does not necessitate that water is a poor solvent for its unfolded state. Indeed, chain-solvent interactions that are marginally more favorable than nonspecific intrachain interactions are beneficial to protein function because they destabilize deleterious misfolded conformations and inter-chain interactions.