N-methylation of lysines is vital to the regulation of many biological processes. It regulates protein activity in one of the two ways: by preventing lysine from undergoing other chemical modifications, or by altering how lysine interacts with its environment. As it stands, methylation alters lysine interactions by increasing its hydrophobicity, as in the progressive substitution of its amine hydrogens by methyl groups decreases the number of strong hydrogen bonds that its amine group can potentially form with its proximal environment. Methyl groups on lysines have also been shown to engage in weak hydrogen bonding, which essentially has the effect of partially countering its enhanced hydrophobicity. Nevertheless, from a theoretical standpoint, the polarization induced by methyl groups can also alter intermolecular interactions. On one hand, methyl groups can increase lysine polarizability and strengthen electrostatic interactions. On the other hand, since methyl groups are more electronegative than the hydrogens they substitute, they can reduce the electron density in the lysine amine group and weaken electrostatic interactions. Here we show using first-principles calculations that lysine methylation weakens electrostatic interactions significantly by several kT. We observe this in both model systems and representative complexes of N-methylated lysines extracted from the Protein Data Bank. In general, these results suggest that the contributions of methyl-induced polarization may also be significant in other types of protein and nucleotide methylation.

Methyl-induced polarization weakens biochemical interactions of N-methylated lysines

2019 Spring National Meeting

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