THE STRUCTURAL DISTRIBUTION OF COOPERATIVE INTERACTIONS IN PROTEINS -ANALYSIS OF THE NATIVE-STATE ENSEMBLE

Cooperative interactions link the behavior of different amino acid res idues within a protein molecule, As a result, the effects of chemical or physical perturbations to any given residue are propagated to other residues by an intricate network of interactions. Very often, amino a cids ''sense'' the effects of perturbations occurring at very distant locations in the protein molecule. In these studies, we have investiga ted by computer simulation the structural distribution of those intera ctions, We show here that cooperative interactions are not intrinsical ly bi-directional and that different residues play different roles wit hin the intricate network of interactions existing in a protein. The e ffect of a perturbation to residue j on residue k is not necessarily e qual to the effect of the same perturbation to residue k on residue j, In this paper, we introduce a computer algorithm aimed at mapping the network of cooperative interactions within a protein. This algorithm exhaustively performs single site thermodynamic mutations to each resi due in the protein and examines the effects of those mutations on the distribution of conformational states. The algorithm has been applied to three different proteins (lambda repressor fragment 6-85, chymotryp sin inhibitor 2, and barnase), This algorithm accounts well for the ob served behavior of these proteins.