Determining the role of hydration forces in protein folding

One of the primary issues in protein folding is determining what forces drive folding and eventually stabilize the native state. A delicate balance exists between electrostatic forces such as hydrogen bonding and salt bridges, and the hydrophobic effect, which are present for both intramolecular protein interactions and intermolecular contributions with the surrounding aqueous environment. This article describes a combined experimental, theoretical, and computational effort to show how the complexity of aqueous hydration can influence the structure, folding and aggregation, and stability of model protein systems. The unification of the theoretical and experimental work is the development or discovery of effective amino acid interactions that implicitly include the effects of aqueous solvent. The authors show that consideration of the full range of complexity of aqueous hydration forces such as many-body effects, long-ranged character of aqueous solvation, and the assumptions made about the degree of protein hydrophobicity can directly impact the observed structure, folding, and stability of model protein systems.