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

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.

Induction of Innate Immune Memory by Engineered Nanoparticles in Monocytes/Macrophages: From Hypothesis to Reality

“…An intermediate of the TCA cycle, α-ketoglutarate, is important for the functions of ten-eleven translocation (TET) proteins involved in DNA methylation ( 56 ) and consequently involved in β-glucan- and BCG-induced long-term reprogramming of myeloid progenitors in the mouse bone marrow ( 29 , 30 ) and is also a cofactor of the JmjC domain-containing histone demethylases (KDMs) ( 57 ). S-adenosyl methionine is a co-substrate of histone and DNA methyl transferases, being the donor of methyl groups ( 58 ). Succinate and fumarate can inhibit demethylation reactions ( 56 ), and in particular fumarate (derived from glutaminolysis for the replenishment of intermediates of the TCA cycle) inhibits the H3K4 demethylase KDM5, favoring the enrichment of H3K4me3 at the promoters of inflammatory genes ( 44 ).…”

Hexacoordinated Tetrel‐Bonded Complexes between TF4 (T=Si, Ge, Sn, Pb) and NCH: Competition between σ‐ and π‐Holes

“…[1][2][3][4] These noncovalent bonds, sometimes generically referred to as σ-hole interactions due to the deficiency of electron density that lies directly opposite a covalent bond in which the bridging atom is involved [5][6][7] have been extensively studied over the last few years and are consequently rather well understood. [9,10] Scores of tetrel bonds have been identified within protein structures, [11][12][13][14][15] and are implicated in the catalytic process of several enzymes. These tetrel bonds differ a bit from the others in this set of noncovalent bonds primarily in that the central atom is typically covalently bonded to four substituents, as compared to only one for a halogen bond or as many as three for a pnicogen bond.…”

“…This sort of bond can, for example, be considered a preliminary step in the very common S N 2 reaction. [9,10] Scores of tetrel bonds have been identified within protein structures, [11][12][13][14][15] and are implicated in the catalytic process of several enzymes. [16][17][18][19][20][21] There is a rapidly growing literature [22][23][24][25][26][27] that has provided a wealth of insights into the chemical and physical phenomena that underlie tetrel bonds.…”

Influence of monomer deformation on the competition between two types of σ-holes in tetrel bonds

“…[1][2][3][4][5][6][7][8][9] Their role is also undisputed in biochemical processes [10][11][12] , for example underpinning the connections between receptors and ligands which facilitate protein transport, or enzymatic catalysis. [13][14][15][16][17][18] A thorough understanding of the fundamental nature of noncovalent interactions and their role in controlling molecular complexes is one of the linchpins for future progress of modern chemistry.…”