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J Phys Chem B. 2016 Sep 22;120(37):9913-21. doi: 10.1021/acs.jpcb.6b07203. Epub 2016 Sep 9.

Exploring the Dependence of QM/MM Calculations of Enzyme Catalysis on the Size of the QM Region.

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Department of Chemistry, University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.


Although QM/MM calculations are the primary current tool for modeling enzymatic reactions, the reliability of such calculations can be limited by the size of the QM region. Thus, we examine in this work the dependence of QM/MM calculations on the size of the QM region, using the reaction of catechol-O-methyl transferase (COMT) as a test case. Our study focuses on the effect of adding residues to the QM region on the activation free energy, obtained with extensive QM/MM sampling. It is found that the sensitivity of the activation barrier to the size of the QM is rather limited, while the dependence of the reaction free energy is somewhat larger. Of course, the results depend on the inclusion of the first solvation shell in the QM regions. For example, the inclusion of the Mg(2+) ion can change the activation barrier due to charge transfer effects. However, such effects can easily be included in semiempirical approaches by proper parametrization. Overall, we establish that QM/MM calculations of activation barriers of enzymatic reactions are not highly sensitive to the size of the QM region, beyond the immediate region that describes the reacting atoms.

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