Organophosphate nerve agents (ONAs) are highly toxic compounds utilized in chemical warfare. Enzymes with mild ONA neutralization capacities have been discovered, and enhancing their function could lead to effective therapeutic and sanitation approaches for ONAs. We have performed molecular dynamics simulations of both wildtype and mutant strains of one such enzyme, organophosphorus acid anhydrase (OPAA), in the presence of VX and VR nerve agents. Our results are compared with recent experimental measurements of OPAA activity towards VX and VR which indicate a trend towards the mutant having higher activity for both ONAs than wildtype. Our simulations corroborate these results by revealing that ONA interactions with a disordered loop distal to the binding pocket are more favorable in the wildtype, while reduced loop interactions in the mutant allow the ONAs to remain proximal to the catalytic center. Importantly, it provides potential enzyme engineering strategies for enhanced catalysis.  In addition, the pattern of ONA contacts observed for non-bonded models of the OPAA metal center differ from those observed in bonded+electrostatics models of the OPAA metal center.

Molecular dynamics simulations of organophosphorus acid anhydrase interactions with V-type organophosphate nerve agents

247th National Meeting (2014)

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