Probing Allosteric Mechanism with Long-Range Rigidity Transmission Across Protein Networks

Allosteric transmission refers to regulation of protein function at a distance. "Allostery" involves regulation and/or signal transduction induced by a perturbation event. Allostery, which has been coined the "second secret of life," is a fundamental property of most dynamics proteins. Most of critical questions surrounding allostery are largely unresolved. One of the key puzzles is to describe the physical mechanism of distant coupled conformational change. Another hot research area surrounding allostery is detection of allosteric pathways or regions (residues) in the protein that are the most critical for transmission of allosteric information. Using techniques inspired by mathematical rigidity theory and mechanical linkages, we have previously proposed a mechanistic model and description of allosteric transmission and an accompanying computational method, the Rigidity Transmission Allostery (RTA) algorithm. The RTA algorithm and method are designed to predict if mechanical perturbation of rigidity, for example, due to ligand binding, at one site of the protein can transmit and propagate across a protein structure and in turn cause a change in available conformational degrees of freedom and a change in conformation at a second distant site, equivalently resulting in allosteric transmission. The RTA algorithm is computationally very fast and can rapidly scan many unknown sites for allosteric transmission, identifying potential novel allosteric sites and quantify their allosteric effect. In this chapter we will discuss the rigidity-based mechanistic model of allosteric communication. As a case illustrative study, we will demonstrate RTA analysis on a G protein coupled receptor (GPCR) human adenosine A2A receptor. Our method gives important implications and a novel prospective for general mechanistic description of allosteric communication.