Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: the case of histone lysine methyltransferase SET7/9.
To elucidate enzyme catalysis through computer simulation, a prerequisite is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio quantum mechanical/molecular mechanical approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9 and its corresponding uncatalyzed reaction in aqueous solution, respectively. Our calculated activation free energy barrier for the enzyme catalyzed reaction is 22.5 kcal/mol, which agrees very well with the experimental value of 20.9 kcal/mol. The difference in potential of mean force between a corresponding prereaction state and the transition state for the solution reaction is computed to be 30.9 kcal/mol. Thus, our simulations indicate that the enzyme SET7/9 plays an essential catalytic role in significantly lowering the barrier for the methyl-transfer reaction step. For the reaction in solution, it is found that the hydrogen bond network near the reaction center undergoes a significant change, and there is a strong shift in electrostatic field from the prereaction state to the transition state, whereas for the enzyme reaction, such an effect is much smaller and the enzyme SET7/9 is found to provide a preorganized electrostatic environment to facilitate the methyl-transfer reaction. Meanwhile, we find that the transition state in the enzyme reaction is a little more dissociative than that in solution.
Wang
Shenglong
S
Department of Chemistry, New York University, New York, New York 10003, USA.
Hu
Po
P
Zhang
Yingkai
Y
D002384:Catalysis; D003198:Computer Simulation; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006657:Histones / Q000138:chemical synthesis / Q000737:chemistry; D006860:Hydrogen Bonding; D008239:Lysine / Q000138:chemical synthesis / Q000737:chemistry; D008745:Methylation; D008956:Models, Chemical; D008958:Models, Molecular; D011496:Protein Methyltransferases; D011789:Quantum Theory; D012996:Solutions / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D006657:Histones; D012996:Solutions; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine