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A Quantum Mechanical Description of Electrostatics Provides a Unified Picture of Catalytic Action Across Methyltransferases

preprint
submitted on 31.05.2019 and posted on 31.05.2019 by Zhongyue Yang, Fang Liu, Adam H. Steeves, Heather Kulik
Methyl transferases (MTases) are a well-studied class of enzymes for which competing enzymatic enhancement mechanisms have been suggested, ranging from structural methyl group C-H···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 multi-scale (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 the majority of cofactor-substrate charge separation is maintained in the TS region, and electrostatic potential is correlated with substrate nucleophilicity (i.e., intrinsic reactivity).

Funding

Burroughs Wellcome Fund Career Award at the Scientific Interface

History

Email Address of Submitting Author

hjkulik@mit.edu

Institution

Massachusetts Institute of Technology

Country

USA

ORCID For Submitting Author

0000-0001-9342-0191

Declaration of Conflict of Interest

The authors declare no conflict of interest.

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