(759d) Force Fluctuations Dictate Kinetics of Biomolecular Systems

A wide array of biological processes occur at rates that vary significantly with applied force. The instantaneous force experienced by individual molecules fluctuates due to thermal noise, leading to concomitant fluctuations in rate constants. We study the effect of these fluctuations on the transition kinetics of force-dependent processes, employing a discretized analytical model to calculate effective rates under fluctuating force. We find that modulating fluctuation time-scales can yield qualitatively different results for overall rates and can dramatically alter the force regime of relevance to the transition. As an illustrative, biologically relevant example, we model the pausing of eukaryotic RNA polymerase as it transcribes nucleosomal DNA. By incorporating fluctuations in the amount of downstream DNA unwrapped from the nucleosome we predict pausing under much higher forces and at more rapid rates than would otherwise be expected, yielding improved agreement with experimental data. Our results emphasize the importance of transient high-force behavior for determining kinetics in the fluctuating environment of a living cell.