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QM/MM-MD simulation of the catalytic hydrolysis of L-captopril by microbial enzyme DapE

Authors : Debodyuti Dutta, Vipin Kumar Mishra and Sabyashachi Mishra*



In the era of ever-increasing anti-microbial resistance, drug re-purposing offers a faster and economic route to the discovery of novel antibiotics. L-Captopril, a widely used angiotensin-converting enzyme inhibitor, has shown inhibitory action towards the microbial enzyme DapE, which is a potential antibiotic target. In this work, a series of biased and unbiased QM/MM-MD simulations has been carried out to investigate the catalytic hydrolysis of L-captopril along a general acid-base hydrolysis mechanism. The QM/MM-MD simulations not only provide an accurate estimation of free energy of activation, but also account for the corrections to the free energy arising from conformational dynamics of the enzyme-substrate complexes. The nucleophilic attack of the hydroxyl ion on the carbonyl group of L-captopril, was found to be the rate-determining step of the catalyzed hydrolysis reaction, which involved activation energy barrier of 15.6 and 13.1 kcal/mol, for the O- and S-coordinated conformations of L-captopril, respectively. Comparing these activation energy barriers with the barriers obtained for the hydrolysis of the natural substrate of DapE enzyme, it is concluded that the catalytic activation of L-captopril by DapE is as efficient as the activation of its natural substrate. Unlike the natural substrate, the activation of L-captopril by DapE yields side products that interrupt the crucial lysine biosynthetic pathway in bacteria.



QM/MM-MD simulation, DapE enzyme, captopril inhibitor