Computational approaches to investigating allostery

Allosteric regulation plays a key role in many biological processes, such as signal transduction, transcriptional regulation, and many more. It is rooted in fundamental thermodynamic and dynamic properties of macromolecular systems that are still poorly understood and are moreover modulated by the cellular context. Here we review the computational approaches used in the investigation of allosteric processes in protein systems. We outline how the models of allostery have evolved from their initial formulation in the sixties to the current views, which more fully account for the roles of the thermodynamic and dynamic properties of the system. We then describe the major classes of computational approaches employed to elucidate the mechanisms of allostery, the insights they have provided, as well as their limitations. We complement this analysis by highlighting the role of computational approaches in promising practical applications, such as the engineering of regulatory modules and identifying allosteric binding sites.