Methylation of certain lysine residues in the N-terminal tails of core histone 
proteins in nucleosome is of fundamental importance in the regulation of 
chromatin structure and gene expression. Such histone modification is catalyzed 
by protein lysine methyltransferases (PKMTs). PKMTs contain a conserved SET 
domain in almost all of the cases and may transfer one to three methyl groups 
from S-adenosyl-L-methionine (AdoMet) to the epsilon-amino group of the target 
lysine residue. Here, quantum mechanical/molecular mechanical molecular dynamics 
and free-energy simulations are performed on human PKMT SET7/9 and its mutants 
to understand two outstanding questions for the reaction catalyzed by PKMTs: the 
mechanism for deprotonation of positively charged methyl lysine (lysine) and 
origin of product specificity. The results of the simulations suggest that 
Tyr-335 (an absolute conserved residue in PKMTs) may play the role as the 
general base for the deprotonation after dissociation of AdoHcy 
(S-adenosyl-L-homocysteine) and before binding of AdoMet. It is shown that 
conformational changes could bring Y335 to the target methyl lysine (lysine) for 
proton abstraction. This mechanism provides an explanation why methyl transfers 
could be catalyzed by PKMTs processively. The free-energy profiles for methyl 
transfers are reported and analyzed for wild type and certain mutants (Y305F and 
Y335F) and the active-site interactions that are of importance for the enzyme's 
function are discussed. The results of the simulations provide important 
insights into the catalytic process and lead to a better understanding of 
experimental observations concerning the origin of product specificity for 
PKMTs.