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Revealing Quantum Mechanical Effects in Enzyme Catalysis with Large-Scale Electronic Structure Simulation

preprint
submitted on 25.09.2018 and posted on 26.09.2018 by Zhongyue Yang, Rimsha Mehmood, Mengyi Wang, Helena W. Qi, Adam H. Steeves, Heather Kulik

Enzymes have evolved to facilitate challenging reactions at ambient conditions with specificity seldom matched by other catalysts. Computational modeling provides valuable insight into catalytic mechanism, and the large size of enzymes mandates multi-scale, quantum mechanical-molecular mechanical (QM/MM) simulations. Although QM/MM plays an essential role in balancing simulation cost to enable sampling with full QM treatment needed to understand electronic structure in enzyme active sites, the relative importance of these two strategies for understanding enzyme mechanism is not well known. We explore challenges in QM/MM for studying the reactivity and stability of three diverse enzymes: i) Mg2+-dependent catechol O-methyltransferase (COMT), ii) radical enzyme choline trimethylamine lyase (CutC), and iii) DNA methyltransferase (DNMT1), which has structural Zn2+ binding sites. In COMT, strong non-covalent interactions lead to long range coupling of electronic structure properties across the active site, but the more isolated nature of the metallocofactor in DNMT1 leads to faster convergence of some properties. We quantify these effects in COMT by computing covariance matrices of by-residue electronic structure properties during dynamics and along the reaction coordinate. In CutC, we observe spontaneous bond cleavage following initiation events, highlighting the importance of sampling and dynamics. We use electronic structure analysis to quantify the relative importance of CHO and OHO non-covalent interactions in imparting reactivity. These three diverse cases enable us to provide some general recommendations regarding QM/MM simulation of enzymes.

Funding

NIH P30-ES002109, Burroughs Wellcome Fund Career Award at the Scientific Interface, Department of Energy Computational Science Graduate Fellowship

History

Email Address of Submitting Author

hjkulik@mit.edu

Institution

Massachusetts Institute of Technology

Country

United States

ORCID For Submitting Author

0000-0001-9342-0191

Declaration of Conflict of Interest

The authors declare no competing interests.

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