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Multiscale Simulations Reveal Distal Allosteric Reprogramming of Pocket Dynamics and Dual Hydrolytic Pathways in Engineered Methyl Parathion Hydrolase
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DOI：10.1021/acs.jpcb.6c01732.png)
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Abstract
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Methyl parathion hydrolase (MPH) is an important organophosphorus (OP) detoxifying enzyme, yet achieving a balance between catalytic activity and thermostability remains a major challenge. Notably, two engineered MPH variants, MPHase-m5a and MPHase-m5b, achieve this balance through predominantly distal substitutions, yet the underlying mechanisms remain unclear. Understanding how such remote mutations simultaneously enhance activity and stability is essential for elucidating MPH function and guiding the design of related detoxifying enzymes. Here, using multiscale simulations, we find that distal mutations do not act locally but instead reshape long-range allosteric networks in MPH, thereby reorganizing active-site pocket dynamics and the catalytic microenvironment. This allosteric remodeling redirects substrate binding toward a catalytically competent pocket and supports a dual hydrolytic mechanism proceeding via either a Zn alpha-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.
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