Rigidity Analysis Identifies Common Features of Allostery

Abstract

Allosteric proteins are remarkable in that they display a dramatic change in chemical affinity at a catalytic site in response to ligand binding at some other distal site. Thus allostery is extremely important biologically as a regulatory mechanism for molecular concentrations in many cellular processes. Structural comparisons of allosteric proteins resolved in both inactive and active states indicate that a variety of structural rearrangement and changes in motions may contribute to general allosteric behavior. We utilize a novel examination of allostery using rigidity analysis of the underlying graph representing a protein structure. Our analysis of paired allosteric proteins resolved in the tense (T) and relaxed (R) states indicate a general global change in rigidity among the two states for 60% of the cases. Typically this change indicates the R state is more rigid than the T state. Different functional classes of allosteric enzymes display departure from this trend. Most notably, signaling proteins tend not to have a change in flexibility. In general it is expected that the coupling of catalytic and regulatory sites is responsible for allosteric behavior. We used a set of allosteric proteins with well-defined heterotropic interactions to test the hypothesis that catalytic and effector sites are structurally coupled. Within this set a rigid path connecting the effector and catalytic sites was observed in 69% of the structures. Such results indicate that rigidity is a possible means by which these distal sites communicate to each other and so contribute to allosteric regulation. This rigidity characterization provides a descriptor to distinguish among different classes of allostery.