Multiscale Allostery: Basic Mechanisms and Versatility in Diagnostics and Drug Design

There were several significant milestones in the last century, from the discovery of the Bohr effect1 to understanding that every dynamic protein is intrinsically allosteric.2, 3 It started slowly and took several, decades-long steps to make progress in the analysis of oxygen binding cooperativity4, 5 before the term allostery was coined in 1961.6 The seminal Monod–Changeux–Jacob work “Allosteric proteins and cellular control systems”7 provided the first formal description of allostery, followed by its implementation in the phenomenological Monod–Wyman–Changeux8 and Koshland–Nemethy–Filmer9 models developed for oligomeric proteins. About a decade later, the key role of protein dynamics10 was formalized in the free-energy landscape view,11, 12 which allows to uniformly describe allosteric regulation of protein function13 in the context of conformational ensembles with transitions between corresponding functional states.3, 14 On the brink of 21st century critical improvements in resolution of major biophysical techniques, such as X-ray crystallography and NMR, turning them, at the same time, into high-throughput approaches delivered atomic details and pictures of dynamics for tens of thousands of proteins and protein assemblies.15 These data revealed the pervasiveness of allostery2 in a wide spectrum of proteins from small single-chain structures to huge molecular assemblies, machines and beyond,16, 17 showing how allostery affects multiple structural and functional facets of biomolecules on different scales. As a result, the number of works on the physical bases, molecular mechanisms, and biological implications of allostery rapidly increased,18 expanding the “allosteric territory” borders19 to include the realm of engineering and design with multiple biomedical applications.15 In particular, allostery became one of the cornerstones of the precision medicine paradigm,18 providing a foundation for development of personalized therapies with distinct specificity and dosage.