COOPERATIVE STRUCTURAL TRANSITIONS INDUCED BY NONHOMOGENEOUS INTRAMOLECULAR INTERACTIONS IN COMPACT GLOBULAR-PROTEINS

The role played by non-homogeneous interactions in stabilizing coopera tive structural changes in proteins was investigated by exhaustive sim ulations of all compact conformations compatible with several well-def ined globule-like shapes in three dimensions. Conformational free ener gies corresponding to the association of residues i and j were compute d both for the unperturbed system, all subject to identical intramolec ular interactions, and for the perturbed system in which a single pair of residues is probed by changing its interactions with an attractive or repulsive interaction. The high packing density leads to strong co upling between residues so that specific interactions between a given pair of residues are accompanied by considerable enthalpy changes. Rel atively weak, about 1-2 kcal/mol, attractive interactions can exert a dramatic effect on the free energy distribution. Usually, central posi tions in the sequence most affect the conformational characteristics. Some of these interaction pairs appear to be capable of effecting majo r conformation transitions because of the high level of cooperativity in the dense state. Effects of repulsive interactions, however, do not depend so strongly on residue pair and cause more localized structura l changes. This approach can suggest more, or less, sensitive loci for amino acid substitution.