A hierarchy of timescales in protein dynamics is linked to enzyme catalysis

The synergy between structure and dynamics is essential to the function of biol. macromols. Thermally driven mol. dynamics on different timescales have been exptl. obsd. or simulated, and a direct link between micro- to milli-​second domain motions and enzymic function has been established. However, very little is understood about the connection of these functionally relevant, collective movements with local at. fluctuations, which are much faster. Here, the authors show that pico- to nano-​second timescale at. fluctuations in hinge regions of adenylate kinase (AK) facilitate the large-​scale, slower lid motions that produce a catalytically competent state. The fast, local mobilities differed between mesophilic and hyperthermophilic AKs, but were strikingly similar at temps. at which enzymic activity and free energy of folding were matched. The connection between different timescales and the corresponding amplitudes of motions in AK and their linkage to catalytic function is likely to be a general characteristic of protein energy landscapes.