Ion pair formation involving methylated lysine side chains: a theoretical study.

Lysine residues with one, two, or three methyl groups substituted on the epsilon-nitrogen atom are found in many proteins. To evaluate the effect of the posttranslational methylation on ion-pair formation we have performed semiempirical and ab initio molecular orbital calculations, using the AM1 method and the 6-31G* basis set, respectively. Combinations of various methylated forms of methylamine and ethylamine with formate, acetate, and dimethyl phosphate were studied as model compounds. This approach allowed us to obtain information relevant to the interaction of the modified Lys residues with carboxylate groups of proteins, and the backbone of nucleic acids. We have found that the interaction energy decreases with an increasing number of methyl groups. Inclusion of a solvent reaction field in the semiempirical calculations gave reasonable values for the interaction energy in aqueous solution, when formate and acetate were the counterions. These studies suggest that, in addition to other factors, a weakening of ionic interactions contributes to the various physiological effects of lysine methylation.