Allosteric Regulation of Enzymatic Catalysis through Mechanical Force

Mechanical force has been increasingly recognized to play crucial roles in regulating various cellular processes, which has inspired wide interest in elucidating the biophysical mechanism underlying these mechanobiological processes. In this work, we investigate the mechanical regulation of enzyme catalysis by developing a residue-resolved computational model capable of describing the full catalytic cycle of enzymes under mechanical force. Intriguingly, for a model enzyme, adenylate kinase, we showed that applying tensile forces with biologically relevant strength can increase the enzymatic activity. Further analysis showed that mechanical tensile force allosterically modifies the global free energy landscape and conformational dynamics of the protein, which then promotes the rate-limiting product release step of the enzymatic cycle. The effect of mechanical allostery on enzyme catalysis depends on the intrinsic conformational propensity of the enzymes. The crucial role of mechanical allostery in enzymatic catalysis elucidated in this work sheds important insights into the biophysical principle of enzymatic regulation and suggests a possible strategy for fine-tuning the functioning dynamics of biological enzymes.