Certain lysine residues on histone tails could be methylated by protein lysine 
methyltransferases (PKMTs) using S-adenosyl-L-methionine (AdoMet) as the methyl 
donor. Since the methylation states of the target lysines play a fundamental 
role in the regulation of chromatin structure and gene expression, it is 
important to study the property of PKMTs that allows a specific number of methyl 
groups (one, two or three) to be added (termed as product specificity). It has 
been shown that the product specificity of PKMTs may be controlled in part by 
the existence of specific residues at the active site. One of the best examples 
is a Phe/Tyr switch found in many PKMTs. Here quantum mechanical/molecular 
mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are 
performed on wild type G9a-like protein (GLP) and its F1209Y and Y1124F mutants 
for understanding the energetic origin of the product specificity and the 
reasons for the change of product specificity as a result of single-residue 
mutations at the Phe/Tyr switch as well as other positions. The free energy 
barriers of the methyl transfer processes calculated from our simulations are 
consistent with experimental data, supporting the suggestion that the relative 
free energy barriers may determine, at least in part, the product specificity of 
PKMTs. The changes of the free energy barriers as a result of the mutations are 
also discussed based on the structural information obtained from the 
simulations. The results suggest that the space and active-site interactions 
around the ε-amino group of the target lysine available for methyl addition 
appear to among the key structural factors in controlling the product 
specificity and activity of PKMTs.