Manipulation of conformational change in proteins by single-residue perturbations.

Using the perturbation-response scanning (PRS) technique, we study a set of 25 proteins that display a variety of conformational motions upon ligand binding (e.g., shear, hinge, allosteric). In most cases, PRS determines single residues that may be manipulated to achieve the resulting conformational change. PRS reveals that for some proteins, binding-induced conformational change may be achieved through the perturbation of residues scattered throughout the protein, whereas in others, perturbation of specific residues confined to a highly specific region is necessary. Overlaps between the experimental and PRS-calculated atomic displacement vectors are usually more descriptive of the conformational change than those obtained from a modal analysis of elastic network models. Furthermore, the largest overlaps obtained by the latter approach do not always appear in the most collective modes; there are cases where more than one mode yields comparable overlap sizes. We show that success of the modal analysis depends on an absence of redundant paths in the protein. PRS thus demonstrates that several relevant modes can be induced simultaneously by perturbing a single select residue on the protein. We also illustrate the biological relevance of applying PRS to the GroEL, adenylate kinase, myosin, and kinesin structures in detail by showing that the residues whose perturbation leads to precise conformational changes usually correspond to those experimentally determined to be functionally important.