Methyl-induced Polarization Destabilizes Non-covalent Interactions of N-methylated Lysines.

Lysine methylation can modify non-covalent interactions by altering lysine's hydrophobicity as well as its electronic structure. While ramifications of the former are documented, the effects of the latter remain largely unknown. Understanding electronic structure is important for determining how biological methylation modulates protein-protein binding, and how artificial methylation impacts experiments in which methylated lysines are used as spectroscopic probes and protein crystallization facilitators. Benchmarked first principles calculations undertaken here reveal that methyl-induced polarization weakens electrostatic attraction of amines with protein functional groups - salt bridges, hydrogen bonds and cation-pi interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Multipole analysis shows that weakened electrostatics is due to altered inductive effects that overcome increased attraction from methyl-enhanced polarizability and dispersion. These effects, due to their fundamental nature, are expected to be present in many cases. Survey of methylated lysines in protein structures reveals several cases where methyl-induced polarization is the primary driver of altered non-covalent interactions, and in these cases destabilizations are found to be in the 0.6-4.7 kT range. The clearest case of where methyl-induced polarization plays a dominant role in regulating biological function is that of the PHD1-PHD2 domain that recognizes lysine methylated-states on histones. These results broaden our understanding of how methylation modulates non-covalent interactions.