Universal QM features of methyltransferases

Methyltransferases (MTases) are among the most ubiquitous regulatory enzymes in the cell, catalyzing gene signaling, protein repair, neurotransmitter regulation, and natural product biosynthesis. Despite being extensively investigated, 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). No broad conclusion can be reached because each study is typically carried out on a single MTase and associated substrate. Additionally, small active-site cluster models have been employed to infer enzymatic mechanisms–the lack of greater protein environment can cause biased description of the enzymatic catalytic function. In this study, we leveraged large-scale electronic structure calculation tools to carry out multi-scale quantum-mechanical/molecular-mechanical simulations on four Class I MTases, including CMTr1, PIMT, PfPMT, and HcgC, which have distinct functions (e.g., protein repair or biosynthesis) and substrate nucleophiles (i.e., C, N, or O). These MTases were systematically identified from the PDB with reasonable resolution (< 2.0 Å) crystal structures that were used to form catalytically competent ternary complexes of the SN2 methyl transfer reaction coordinate. While CH···X HBs stabilize all reactant complexes, no universal TS stabilization role is found for these interactions in MTases. A convergent catalytic picture is instead obtained through analysis of charge transfer and electrostatics. Instead of neutralization, charge separation between SAM cofactor and the substrate is found 40-75% maintained in the TS region, leading to favorable electrostatic interactions between the reacting fragments during the rate-limiting barrier climbing event. In addition, we also observed a good correlation between the electrostatic potential experienced by the transferring methyl group and the substrate nucelophilicity (i.e. intrinsic substrate reactivity). This indicates that enzymatic electrostatic environment compensates for otherwise chemically challenging methyl transfer reactions, explaining the similar experimental barriers across all four MTases.


Check out our recent publication, Z. Yang, F. Liu, A. H. Steeves, and H. J. Kulik, J. Phys. Chem. Lett. ASAP here!

About Us

The Kulik group focuses on the development and application of new electronic structure methods and atomistic simulations tools in the broad area of catalysis.

Our Interests

We are interested in transition metal chemistry, with applications from biological systems (i.e. enzymes) to nonbiological applications in surface science and molecular catalysis.

Our Focus

A key focus of our group is to understand mechanistic features of complex catalysts and to facilitate and develop tools for computationally driven design.

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