Perspective: How Fast Dynamics Affect Slow Function in Protein Machines

Internal motions in proteins take place on a broad rangeof time-and space-scales. The potential roles of these dynamics in the biochemicalfunctions of proteins have intrigued biophysicists for many years,and multiple mechanisms to couple motions to function have been proposed.Some of these mechanisms have relied on equilibrium concepts. Forexample, the modulation of dynamics was proposed to change the entropyof a protein, hence affecting processes such as binding. This so-calleddynamic allostery scenario has been demonstrated in several recentexperiments. Perhaps even more intriguing may be models that involveout-of-equilibrium operation, which by necessity require the inputof energy. We discuss several recent experimental studies that exposesuch potential mechanisms for coupling dynamics and function. In Brownianratchets, for example, directional motion is promoted by switchinga protein between two free energy surfaces. An additional exampleinvolves the effect of microsecond domain-closure dynamics of an enzymeon its much slower chemical cycle. These observations lead us to proposea novel two-time-scale paradigm for the activity of protein machines:fast equilibrium fluctuations take place on the microsecond-millisecondtime scale, while on a slower time scale, free energy is investedin order to push the system out of equilibrium and drive functionaltransitions. Motions on the two time scales affect each other andare essential for the overall function of these machines.