Ruth Nussinov

In 1999 Ruth Nussinov originated the groundbreaking concept that all conformations preexist—even if the crystal captures only one—and evolution harnesses their dynamic transitions for function, dispelling the dogma that only the wild-type shape is relevant. she pioneered a vastly different scenario from the-then dogma of two, “open” and “closed” conformations proposed by Monod, Wyman, and Changeux. She formulated the concept that there is not one folded form, nor two—as they suggested—but many different forms, and in equilibrium, the system keeps jumping between them, and that this barrier-crossing is function. Her concept is crucial since it explained that rather than the ligand inducing a conformational change (as in induced fit), the ligand can select a preexisting (sparse, non-minimal energy) conformation in the system that may be better suited to dock it, with minor optimization. Upon binding the ligand, the equilibrium will keep producing more of this conformation to compensate, which she stated (also in 1999), is the allosteric effect. This innovative concept as an alternative to the “induced fit” text-book model explains the mechanism of molecular recognition. The dynamic shifts among conformations help explain catalysis (2000), kinase activation, allosteric regulation, signaling and drug discovery, which are her current focus. Her concept is now widely established. As she and others have shown since, it helps unravel diverse processes, recently addressing puzzling questions like how same-gene mutations can promote both cancer and neurodevelopmental pathologies.