Protein dynamics─the fluctuating nature of protein structure once described by Gregorio Weber as "kicking and screaming"─is understood to be an intrinsic feature of proteins and their function. Yet it is often difficult to pin down exactly how those dynamics assist function. Allosteric regulation is a widespread protein function that was once seen to operate solely through conformational change. Over the last two decades, a series of experimental studies has shown that thermally activated, rapid-time scale dynamics can underlie allosteric ligand binding cooperativity, even in the absence of conformational change. This concept is known as "dynamic allostery", in which localized dynamics represent conformational entropy that can effectively serve as a set of thermodynamic "nano-levers". Here, we review these studies and their collective finding: that changes in the amplitudes of picosecond-nanosecond timescale side-chain dynamics can exert a large entropic driving force in protein binding events. The studies require NMR relaxation measurements of methyl "order parameters" (O2axis). We focus on the recent example from Sgt2, a chaperone in yeast's guided tail-anchoring protein pathway. Sgt2 harbors an intrinsically disordered C-terminal tail that allosterically enhances side-chain dynamics in other domains, which in turn abrogates binding to partner Get4/5. Motivated by this example, order parameters are explained in simple terms and discussed empirically to raise confidence in them as meaningful reporters of local motion. Specific studies are highlighted to show that different proteins utilize distinct dynamic strategies for allosteric coupling. Finally, the surprising role of disordered tails in controlling dynamic allostery is discussed.
Lee et al. (Wed,) studied this question.