Quantum Mechanical Description of Electrostatics Provides a Unified Picture of Catalytic Action Across Methyltransferases
Name
A_Quantum_Mechanical_Description_of_Electrostatics_Provides_a_Unified_Picture_of_Catalytic_Action_Across_Methyltransfera_v1.pdf
Description
Submitted version
Size
5.79 MB
Format
Adobe PDF
Checksum (MD5)
5112385b33ab05735d0753413158e75b
Author(s)
Yang, Zhongyue
Liu, Fang
Steeves, Adam H
Kulik, Heather J
Date Issued
2019
Journal
Journal of Physical Chemistry Letters
Publisher
American Chemical Society (ACS)
Version
Original manuscript
Abstract
© 2019 American Chemical Society. Methyl transferases (MTases) are a well-studied class of enzymes for which competing enzymatic enhancement mechanisms have been suggested, ranging from structural methyl group CH···X hydrogen bonds (HBs) to electrostatic- and charge-transfer-driven stabilization of the transition state (TS). We identified all Class I MTases for which reasonable resolution (<2.0 Å) crystal structures could be used to form catalytically competent ternary complexes for multiscale (i.e., quantum-mechanical/molecular-mechanical or QM/MM) simulation of the SN2 methyl transfer reaction coordinate. The four Class I MTases studied have both distinct functions (e.g., protein repair or biosynthesis) and substrate nucleophiles (i.e., C, N, or O). While CH···X HBs stabilize all reactant complexes, no universal TS stabilization role is found for these interactions in MTases. A consistent picture is instead obtained through analysis of charge transfer and electrostatics, wherein much of cofactor-substrate charge separation is maintained in the TS region, and electrostatic potential is correlated with substrate nucleophilicity (i.e., intrinsic reactivity).
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1021/acs.jpclett.9b01555
