Examining Reaction Mechanisms of Catechol O-Methyltransferase

Abstract

The enzyme catechol O-methyltransferase (COMT) catalyzes methyl transfer reaction from S-adenosylmethionine (SAM) to a catechol molecule. There has been hot debate on various proposed mechanisms that aim to explain the catalytic power of COMT. In this study, we have utilized a theoretical approach to examine the effect of two of the proposed mechanisms: the compression mechanism and the electrostatic preorganization mechanism. We prepared our system from the crystal structure of COMT. Quantum mechanics/molecular mechanics(QM/MM) simulations were performed using the CHARMM forcefield on the bulk protein and the PM6 semi empirical method on the SAM and the catechol molecules. We used the transition path sampling (TPS) method to sample simulation trajectories that capture the chemical step of the COMT methyl transfer reaction. Committor analysis was then used to find transition state structures for TPS trajectories. Starting from the transition state structures, we used a committor distribution analysis method to find the reaction coordinate of the reaction. We were then able to examine the effect of compression motions from the bulk protein to the active site by checking if these motions are coupled with the reaction coordinate. By extracting Mulliken charges from TPS trajectories, we were able to calculate the electric field of the enzyme, and examine its effect on the reaction progress.