Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases

Molecular dynamics and hybrid quantum mechanics/molecular mechanics have been used to investigate the mechanisms of (+)AdoMet methylation of protein-Lys-NH2 catalyzed by the lysine methyltransferase enzymes: histone lysine monomethyltransferase SET7/9, Rubisco large-subunit dimethyltransferase, viral histone lysine trimethyltransferase, and the Tyr245Phe mutation of SET7/9. At neutrality in aqueous solution, primary amines are protonated. The enzyme reacts with Lys-NH3+ and (+)AdoMet species to provide an Enz center dot Lys-NH3+center dot(+)AdoMet complex. The close positioning of two positive charges lowers the pK(a) of the Lys-NH3+ entity, a water channel appears, and the proton escapes to the aqueous solvent; then the reaction Enz center dot Lys-NH2 center dot(+)AdoMet -> Enz center dot Lys-N(Me)H-2(+)center dot AdoHcy occurs. Repeat of the sequence provides dimethylated lysine, and another repeat yields a trimethylated lysine. The sequence is halted at monomethylation when the conformation of the Enz center dot Lys-N(Me)H-2(+)center dot(+)AdoMet has the methyl positioned to block formation of a water channel. The sequence of reactions stops at dimethylation if the conformation of Enz center dot Lys-N(Me)(2)H+center dot(+)AdoMet has a methyl in position, which forbids the formation of the water channel.