S-adenosylmethionine (AdoMet)-based methylation is integral to metabolism and signaling. AdoMet-dependent methyltransferases belong to multiple distinct classes and share a catalytic mechanism that arose through convergent evolution; however, fundamental determinants underlying this shared methyl transfer mechanism remain undefined. A survey of high-resolution crystal structures reveals that unconventional carbon-oxygen (CH···O) hydrogen bonds coordinate the AdoMet methyl group in different methyltransferases irrespective of their class, active site structure, or cofactor binding conformation. Corroborating these observations, quantum chemistry calculations demonstrate that these charged interactions formed by the AdoMet sulfonium cation are stronger than typical CH···O hydrogen bonds. Biochemical and structural studies using a model lysine methyltransferase and an active site mutant that abolishes CH···O hydrogen bonding to AdoMet illustrate that these interactions are important for high-affinity AdoMet binding and transition-state stabilization. Further, crystallographic and NMR dynamics experiments of the wild-type enzyme demonstrate that the CH···O hydrogen bonds constrain the motion of the AdoMet methyl group, potentially facilitating its alignment during catalysis. Collectively, the experimental findings with the model methyltransferase and structural survey imply that methyl CH···O hydrogen bonding represents a convergent evolutionary feature of AdoMet-dependent methyltransferases, mediating a universal mechanism for methyl transfer.
Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS(+)···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.3 and 4.3 kcal/mol, with the strongest interaction occurring for X = F. The binding is strengthened by a factor of 2-10 in charged XH2S(+)···NH3 complexes, reaching a maximum of 37 kcal/mol for X = F. The binding is weakened to some degree when the H atoms are replaced by methyl groups in XMe2S(+)···NH3. The source of the interaction in the charged systems, like their neutral counterparts, is derived from a charge transfer from the N lone pair into the σ*(SX) antibonding orbital, supplemented by a strong electrostatic and smaller dispersion component. The binding is also derived from small contributions from a CH···N H-bond involving the methyl groups, which is most notable in the weaker complexes.
Previous work has documented the ability of the P atom to form a direct attractive noncovalent interaction with a N atom, based in large measure on the charge transfer from the N lone pair into the σ* antibonding orbital of the P-H that is turned away from the N atom. The present work considers whether other atoms, namely, O and S, can also participate as electron donors, and in which bonding environments. Also considered are the π-systems of multiply bonded C atoms. Unlike an earlier observation that the interaction is unaffected by the nature of the electron-acceptor atom, there is strong sensitivity to the donor. The P···D binding energy diminishes in the order D = NH(3) > H(2)CO > H(2)CS > H(2)O > H(2)S, different from the patterns observed in both H and halogen bonds. The P···D interactions are comparable to, and in some cases stronger than, the analogous H-bonds formed by HOH as proton donor. The carbon π systems form surprisingly strong P···D complexes, augmented by the back-donation from the P lone pair to the C-C π* antibond, which surpass the strengths of H-bonds, even some with HF as proton donor.
Cl, S, and P atoms have previously been shown as capable of engaging in a noncovalent bond with the N atom on another molecule. The effects of substituents B on the former atoms on the strength of this bond are examined, and it is found that the binding energy climbs in the order B = CH(3) < NH(2) < CF(3) < OH < Cl < NO(2) < F. However, there is some variability in this pattern, particularly for the NO(2) group. The A···N bonds (A = Cl, S, P) can be quite strong, amounting to as much as 10 kcal/mol. The binding energy arises from approximately equal contributions from its induction and electrostatic components, although the former becomes more dominant for the stronger bonds. The induction energy is due in large measure to the transfer of charge from the N lone pair to a B-A σ* antibonding orbital of the electron-acceptor molecule containing Cl, S, or P. These A···N bonds typically represent the lowest-energy structure on each potential energy surface, stronger than H-bonds such as NH···F, CH···N, or SH···N.
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