LOCAL INTERACTIONS AND THE OPTIMIZATION OF PROTEIN-FOLDING

The role of local interactions in protein folding has recently been th e subject of some controversy. Here we investigate an extension of Zwa nzig's simple and general model of folding in which local and nonlocal interactions are represented by functions of single and multiple conf ormational degrees of freedom, respectively. The kinetics and thermody namics of folding are studied for a series of energy functions in whic h the energy of the native structure is fixed, but the relative contri butions of local and nonlocal interactions to this energy are varied o ver a broad range. For funnel shaped energy landscapes, we find that 1 ) the rate of folding increases, but the stability of the folded state decreases, as the contribution of local interactions to the energy of the native structure increases, and 2) the amount of native structure in the unfolded state and the transition state vary considerably with the local interaction strength. Simple exponential kinetics and a wel l-defined free energy barrier separating folded and unfolded states ar e observed when nonlocal interactions make an appreciable contribution to the energy of the native structure; in such cases a transition sta te theory type approximation yields reasonably accurate estimates of t he folding rate. Blimps in the folding funnel near the native state, w hich could result from desolvation effects, side chain freezing, or th e breaking of normative contacts, significantly alter the dependence o f the folding rate on the local interaction strength: the rate of fold ing decreases when the local interaction strength is increased beyond a certain point. A survey of the distribution of strong contacts in th e protein structure database suggests that evolutionary optimization h as involved both kinetics and thermodynamics: strong contacts are enri ched at both very short and very long sequence separations. (C) 1997 W iley-Liss, Inc.