Revealing quantum mechanical effects in enzyme catalysis with large-scale electronic structure simulation
Name
c8re00213d.pdf
Size
6.38 MB
Format
Adobe PDF
Checksum (MD5)
efd98d135d7f1558ee5df369c99edbdb
Author(s)
Yang, Zhongyue
Mehmood, Rimsha
Wang, Mengyi
Qi, Helena Wen
Steeves, Adam H.
Kulik, Heather Janine
Date Issued
November 2018
Journal
Reaction Chemistry & Engineering
Publisher
Royal Society of Chemistry
Citation
Yang, Zhongyue, Rimsha Mehmood, Mengyi Wang, Helena W. Qi, Adam H. Steeves, and Heather J. Kulik. “Revealing Quantum Mechanical Effects in Enzyme Catalysis with Large-Scale Electronic Structure Simulation.” Reaction Chemistry & Engineering (November 2019).
Version
Final published version
Abstract
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 the 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) Mg[supercript 2+]-dependent catechol O-methyltransferase (COMT), ii) radical enzyme choline trimethylamine lyase (CutC), and iii) DNA methyltransferase (DNMT1), which has structural Zn[superscript 2+] 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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Terms of Use
Creative Commons Attribution Noncommercial 3.0 unported license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1039/c8re00213d
