AbstractOn the basis of the perturbation nature of allosteric communication, a computational framework is proposed for estimating the energetics of signaling caused by the ligand binding and mutations. The perturbations are modelled as alterations of the strenght of interactions in the protein contact network in the binding sites and neighborhoods of mutated residues. The combination of protein harmonic modelling with effect of perturbations and the estimate of local partition functions allow one to evaluate the energetics of allosteric communication at single residue level. The potential allosteric effect of a protein residue position, modulation range, is given by the difference between responses to stabilizing and destabilizing mutations. We show a versatility of the approach on three case studies of proteins with different mechanisms of allosteric regulation, testing it on their known regulatory and functional sites. Allosteric Signaling Maps (ASMs) obtained on the basis of residue-by-residue scanning are proposed as a comprehensive tool to explore a relationship between mutations allosterically modulating protein activity and those that mainly affect protein stability. Analysis of ASMs shows distance dependence of the mode switching in allosteric signaling, emphasizing the role of domains/subunits in protein allosteric communication as elements of a percolative system. Finally, ASMs can be used to complement and tune already existing signaling and to design new elements of allosteric regulation.SignificanceUniversality of allosteric signaling in proteins, molecular machines, and receptors and great advantages of prospected allosteric drugs in highly specific, non-competitive, and modulatory nature of their actions call for deeper theoretical understanding of allosteric communication. In the energy landscape paradigm underliying the molecular mechanisms of protein function, allosteric signalling is the result of any perturbation, such as ligand binding, mutations, intermolecular interactions etc. We present a computational model, allowing to tackle the problem of modulating the energetics of protein allosteric communication. Using this method, Allosteric Signaling Maps (ASMs) are proposed as an approach to exhaustively describe allosteric signaling in the protein, making it possible to take protein activity under allosteric control.
Allosteric Control of O2 Reactivity in Rieske Oxygenases
