On the Nature of the Transition State in Catechol O-Methyltransferase. A Complementary Study Based on Molecular Dynamics and Potential Energy Surface Explorations

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• 作者：Maite Roca ; Juan André ; s ; Vicent Moliner ; Iñ ; aki Tuñ ; ó ; n ; and Juan Bertr&aacute ; n
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：August 3, 2005
• 年：2005
• 卷：127
• 期：30
• 页码：10648 - 10655
• 全文大小：176K
• 年卷期：v.127,no.30(August 3, 2005)
• ISSN：1520-5126

文摘

The way in which enzymes influence the rate of chemical processes is still a question of debate.The protein promotes the catalysis of biochemical processes by lowering the free energy barrier incomparison with the reference uncatalyzed reaction in solution. In this article we are reporting static anddynamic aspects of the enzyme catalysis in a bimolecular reaction, namely a methyl transfer fromS-adenosylmethionine to the hydroxylate oxygen of a substituted catechol catalyzed by catecholO-methyltransferase. From QM/MM optimizations, we will first analyze the participation of the environmenton the transition vector. The study of molecular dynamics trajectories will allow us to estimate thetransmission coefficient from a previously localized transition state as the maximum in the potential ofmean force profile. The analysis of the reactive and nonreactive trajectories in the enzyme environmentand in solution will also allow studying the geometrical and electronic changes, with special attention tothe chemical system movements and the coupling with the environment. The main result, coming fromboth analyses, is the approximation of the magnesium cation to the nucleophilic and the hydroxyl group ofthe catecholate as a result of a general movement of the protein, stabilizing in this way the transition state.Consequently, the free energy barrier of the enzyme reaction is dramatically decreased with respect to thereaction in solution.