Computing allostery: from the understanding of biomolecular regulation and the discovery of cryptic sites to molecular design

: The concept of allostery has become a central tenet in the study of biological systems. In parallel, the discovery of allosteric drugs is generating new opportunities to selectively modulate difficult targets involved in pathologic mechanisms. Molecular simulations can provide atomistically detailed insight into the processes involved in allosteric regulation and signaling, and at the same time, they have the potential to unveil regulatory hotspots or cryptic sites that are not immediately evident from the analysis of static structures. In this context, computational approaches should be able to connect the study of allosteric regulation at different scales to the possibility of leveraging this knowledge to expand the chemical space of new, active drugs. Here, we will discuss recent advances in the study of allosteric regulation via computational methods and connect the mechanistic knowledge generated to the possibility of designing new small molecules that can tweak the functions of their receptors.