Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases.

Raymond C Trievel,Steve Scheiner

doi:10.3390/molecules23112965

Raymond C Trievel, Steve Scheiner

Open Access

https://doi.org/10.3390/molecules23112965

Copy DOI

Abstract

Tetrel bonds represent a category of non-bonding interaction wherein an electronegative atom donates a lone pair of electrons into the sigma antibonding orbital of an atom in the carbon group of the periodic table. Prior computational studies have implicated tetrel bonding in the stabilization of a preliminary state that precedes the transition state in SN2 reactions, including methyl transfer. Notably, the angles between the tetrel bond donor and acceptor atoms coincide with the prerequisite geometry for the SN2 reaction. Prompted by these findings, we surveyed crystal structures of methyltransferases in the Protein Data Bank and discovered multiple instances of carbon tetrel bonding between the methyl group of the substrate S-adenosylmethionine (AdoMet) and electronegative atoms of small molecule inhibitors, ions, and solvent molecules. The majority of these interactions involve oxygen atoms as the Lewis base, with the exception of one structure in which a chlorine atom of an inhibitor functions as the electron donor. Quantum mechanical analyses of a representative subset of the methyltransferase structures from the survey revealed that the calculated interaction energies and spectral properties are consistent with the values for bona fide carbon tetrel bonds. The discovery of methyl tetrel bonding offers new insights into the mechanism underlying the SN2 reaction catalyzed by AdoMet-dependent methyltransferases. These findings highlight the potential of exploiting these interactions in developing new methyltransferase inhibitors.

Highlights

Methyltransferases represent a ubiquitous class of enzymes that methylate a vast array of small molecules and macromolecules and participate in numerous biological processes, including metabolism, signal transduction, and gene expression [1,2,3]
No methyl tetrel bonding was observed between AdoMet and residues in the methyltransferases because the active sites of these enzymes preferentially orient the methyl group for nucleophilic attack by the methyl acceptor substrate
CH···O hydrogen bonding between the AdoMet methyl group and active site residues was observed in a high proportion of methyltransferase structures, as these interactions mediate substrate recognition by the enzymes and promote the alignment of the methyl group during the SN 2 reaction [18,43]

Summary

Introduction

Methyltransferases represent a ubiquitous class of enzymes that methylate a vast array of small molecules and macromolecules and participate in numerous biological processes, including metabolism, signal transduction, and gene expression [1,2,3]. The reaction mechanism of these enzymes has been a subject of intense study for over 40 years [5] and has led to the proposal of several different models for catalysis These models include (1) compression or compaction of nucleophile, electrophile, and leaving groups along the reaction coordinate [6,7,8,9], (2) formation of near attack conformers (NACs) that align the nucleophile and methyl. Molecules 2018, 23, 2965 group in a productive geometry for the SN 2 reaction [10,11,12,13], (3) electrostatic pre-organization within the active site that promotes methyl transfer [14,15], and (4) cratic effects involving the free energy of association of the substrates in a catalytically favorable alignment within the active site [16,17] Despite these models, the methyltransferase mechanism remains a topic of active debate

Methods

Results

Discussion

Conclusion