From elucidating mechanisms of allosteric signaling to designing allosteric drugs and biologics

Allostery is a pervasive phenomenon underlies a multitude of cellular processes. We have previously developed a Structure-Based Statistical Mechanical Model of Allostery (SBSMMA) to quantitatively describe the causality and energetics of allosteric signaling due to perturbations such as ligand binding, mutations, disorder-order transition and post-translational modifications. The computational model was implemented in the AlloSigMA server and AlloMAPS database, which allow one to explore allosteric effects of perturbations in form of the exhaustive Allosteric Signaling/Probing Map (ASM/APM), to identify potential allosteric sites, and to facilitate effector design. Here, we demonstrate some recent work on applying our broadly applicable framework to different aspects of allostery. First, analysis of communication between different sites/regions of the Spike protein from SARS-CoV-2 revealed mutations harbored by variants of concern, as well as glycosylation, that originate strong signaling to the distant receptor-binding domain despite the separation. Using reverse perturbation of allosteric communication and ASM/APM, we identified potential druggable sites that can induce tunable allosteric responses in different functional regions of Spike. Second, while the strengths of allosteric medicines are widely recognized, rational design of effectors remains a challenging problem. We demonstrated with GPCRs and kinases that effector design should begin with the search/design for latent/non-natural binding sites, followed by fragment-based design of ligands, and consequently mutual adjustments of site-ligand pairs to obtain and tune the desired binding affinity and allosteric signals. Third, rapid progress in harnessing allostery calls for an understanding of how communication is established by different structural elements and how it can be modified. We obtained a picture of conserved allosteric communication characteristic in major folds, alterations of structure-driven signaling via sequence-determined divergence to distinct functions, and its diversification in multi-domain proteins and oligomers, which will facilitate engineering/design of allosteric communication.