The reaction mechanism of multiple lysine methylation by S-adenosylmethionine (as modeled by sulfonium ion) has been studied by means of ab initio and DFT calculations. The barriers of uncatalyzed reaction in gas phase are somewhat lower and the reaction profile resembles typical SN2 reactions, whereas the reactions present significantly higher barriers in dielectric media. The hydrogen bond contribution of three residues in the active site of the Rubisco large subunit methyltransferases to monomethylation reaction has also been evaluated by B3LYP/6-31G* and ONIOM MP2: B3LYP calculations. At the ONIOM (MP2:B3LYP) level, the reaction barrier was predicted to be 82.8 kJ/mol, which is in excellent agreement with the activation barrier of 87.4 kJ/mol estimated from the experimental value. The enzymes can not yield special stabilization on the transition state, however they provide a solvent-free room for the substrate (sulfonium ion and amine) and can bring the nucleophile and the electrophile together through the nearby residues, therefore facilitating the methylation processes.

Key words: lysine methylation, methyltransferase, adoMet, ONIOM, ab initio