Multiscale Simulations Reveal Distal Allosteric Reprogramming of Pocket Dynamics and Dual Hydrolytic Pathways in Engineered Methyl Parathion Hydrolase

-bound water molecule or a bridging hydroxide. In parallel, long-range allosteric communication modulates enzyme flexibility in a temperature-dependent manner, thereby tuning thermostability. Distinct mechanistic modes are suggested: MPHase-m5a enhances thermostability through local rigidification, whereas MPHase-m5b preserves productive dynamics to achieve higher catalytic efficiency. These findings highlight distal allostery as a useful design principle for simultaneously optimizing catalytic activity and thermostability in detoxifying hydrolases.