We present how an ensemble of reaction paths may be constructed with the help of hybrid QM-MM molecular dynamics simulation interfaced with transition path sampling for an enzyme catalyzed reaction with a high free energy barrier. We also show how to choose a few appropriate collective variables and combine them in linear or non-linear fashion to derive an optimum reaction coordinate using artificial neural network, likelihood maximization, markov state model and extended auto encoder analysis. Application to the rate determining proton transfer reaction catalyzed by human carbonic anhydrase II results in a quantitative match of our estimated rate constant to the experimental value. We also demonstrate how the actual chemical event competes with other key mechanisms such as coordination dynamics of the catalytic Zn<sup>2+</sup> ion or the sidechain dynamics of a key residue His-64 at and near the active site.

From reaction coordinates to free energy and kinetics of an enzyme catalyzed proton transfer reaction

ACS Spring 2022

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