A QM/MM exploration of the potential energy surface of pyruvate to lactate transformation catalyzed by LDH.: Improving the accuracy of semiempirical descriptions

We present a QM/MM study of the potential energy surface of the pyruvate to lactate transformation catalyzed by L-lactate dehydrogenase. The transformation involves a hydride and a proton transfer which are followed by means of the corresponding antisymmetric combination of the distances from the hydrogen atom to the donor and the acceptor atoms. To discriminate among the possible reaction mechanisms we have considered different improvements of the AM1/MM description: reoptimization of the van der Waals parameters and inclusion of corrections to the QM energy associated with both transfer coordinates. The QM subsystem has been also enlarged to include charge-transfer effects from the substrate to some specific residues. In our best treatment, the transformation is described as a concerted process through a single transition structure in which the hydride transfer is more advanced than the proton transfer. From the methodological point of view, the correction schemes tested here improve the quality of the semiempirical potential energy surface although they also present deficiencies attributed to consideration of the proton and hydride transfer corrections as separable ones.