Toward Comprehensive Allosteric Control over Protein Activity.

ABSTRACT

Universality of allosteric signaling in proteins, molecular machines, and receptors complemented by the great advantages of prospected allosteric drugs in the highly specific, non-competitive, and modulatory nature of their actions calls for deeper theoretical understanding of allosteric communication. We present a computational model that makes it possible to tackle the problem of modulating the energetics of protein allosteric communication. In the context of the energy landscape paradigm, allosteric signaling is always a result of perturbations, such as ligand binding, mutations, and intermolecular interactions. The calculation of local partition functions in the protein harmonic model with perturbations allows us to evaluate the energetics of allosteric communication at the single-residue level. In this framework, Allosteric Signaling Maps are proposed as a tool to exhaustively describe allosteric communication in the protein, to tune already existing signaling, and to design new elements of regulation for taking the protein activity under allosteric control.