Allosteric Protein Chemical Shift Perturbations are Ubiquitous

While allosteric protein function has been appreciated for decades, the ubiquity of conformational shifts, particularly those distant from the interaction interface, has not been broadly characterized. For example, ligand binding frequently triggers allosteric effects far from the interaction interface, yet the prevalence of these conformational shifts underpinning protein function remain poorly documented. We systematically assessed the generality of allosteric effects as monitored by NMR Chemical Shift Perturbations (CSPs) distant from the interaction interface. In a set of 139 protein-protein complexes, a striking 74% of all significant CSPs are non-local to the binding site. Notably, more than 35% of significant CSPs outside the binding site occur in residues for which the shortest receptor-ligand interatomic distance is more than 10 [A]. Every protein analyzed exhibits a significant fraction (> 8%) of CSPs distant from the binding site. This analysis across a large number of protein structures demonstrates and documents that structural plasticity is a ubiquitous and fundamental property of proteins. Significance StatementStudies of protein dynamics have had a profound impact on biology. Ruth Nussinov famously postulated that multiple protein conformations preexist in dynamic equilibrium, with interconversions that mediate function. While conformational flexibility has been characterized in many specific case studies, the extent to which structural plasticity can be considered a fundamental and ubiquitous property of proteins remains poorly documented. We address a central question: how common is protein structural plasticity? To do so, we compiled a database of protein-protein and protein-peptide complexes with NMR chemical shift data for both bound (holo) and unbound (apo) states. These data reveal the widespread prevalence of long-range structural perturbations induced by ligand binding, demonstrating that structural plasticity is a pervasive and fundamental property of proteins.