**5. Conclusions**

The survey of AdoMet-bound methyltransferase structures in the PDB uncovered a number of geometries that strongly indicate the presence of methyl tetrel bonding to electronegative atoms in small molecule inhibitors, solvent molecules, and ions. The C···X distances between the AdoMet methyl carbon atom and the Lewis base vary over a wide range, but all of the C···O interactions reported from this survey are less than 3.25 Å, with some distances as short as 2.5 Å. Further, the Lewis base is located close to the extension of the S–CH3 bond of AdoMet, with θ(S–C···O) angles within 20◦ of linearity. QM analysis of a selected set of these interactions revealed unequivocal evidence of methyl tetrel bonds, rather than what might naively be considered a trifurcated CH···O hydrogen bond. The interaction energies of these selected tetrel bonds varied between −5 and −9 kcal/mol, comparable to or stronger than the paradigmatic hydrogen bond between a pair of water molecules (−5.8 kcal/mol). In the case of a Lewis base bearing a full negative charge, the tetrel bond energy was amplified to more than −60 kcal/mol. It is thus clear that our understanding of the forces present within biological systems must include tetrel bonding on the same footing as the venerable hydrogen bond. Finally, the discovery of AdoMet methyl tetrel bonding in methyltransferases illustrates that this interaction may have a fundamental role in the catalytic mechanism of these enzymes and thus merits further investigation. An understanding of this novel interaction can be applied in structure-guided design of potent inhibitors of methyltransferases implicated in disease.

**Author Contributions:** R.C.T. conducted the PDB survey for methyl tetrel bonding, and S.S. performed the QM calculations and analysis. R.C.T. and S.S. wrote the paper.

**Funding:** These studies were supported by NSF grant CHE-1508492 to R. Trievel.

**Acknowledgments:** We wish to thank S. Horowitz for his insightful comments and feedback on this work.

**Conflicts of Interest:** The authors declare no conflict of interest.

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