Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II

91-POS Board 44 In Silico Study on the Putative Methylation Mechanism Catalyzed by the Palmitic Acid Binding to the Catechol O-Methyltransferase Wei-Hsiang Weng 1 , Chin-Hung Liu 2 , Tony J.-F. Lee 1,2 , Hao-Jen Hsu 1 . 1 Department of Life Sciences, Tzu Chi University, Hualien City, Taiwan, 2 Institutes of Medical Sciences, Tzu Chi University, Hualien City, Taiwan. Catechol O-methyltransferase (COMT) is an enzyme that catalyzes the donation of a methyl group from S-adenosyl methionine (SAM) to catecholamines. This transfer of methyl group initiates one of the major degradation pathways of catecholamine transmitters, such as dopamine, norepinephrine and epinephrine. In addition, COMT also plays a crucial role in the metabolism of catechol used in the treatment of hypertension, asthma, and Parkinson’s disease. Previous report by Tony J.-F. Lee in 2011 has verified that palmitic acid methyl ester (PAME) can cause vasorelaxation through opening the voltage dependent K + channels on vascular smooth muscle cells. Hence, we attempted to find out the methylation mechanism of palmitic acid (PA) catalyzed by COMT, using molecular docking combining MD simulations. Due to lack of the structure of PA binding to COMT, the complex structure of 3,5-dinitrocatechol (DNC) bound with SAM and COMT (PDB: 3A7E) was used as a template for molecular docking. Three various compounds including DNC (as an inhibitor), 3,4-Dihydroxyacetophenone (DHAP, as a positive control) and PA were docked with apo-COMT protein respectively for comparison. The most preferable complex structures were also determined to run 200 ns MD simulations under physiological conditions to study the interactions between them. The binding free energy (Δ G bind ) calculated by MM/PBSA technique showed that Δ G bin d of DNC is the lowest than that of DHAP and PA. The MD simulations showed that the distance between the hydroxyl group of PA and the methyl group near sulfur atom is increasingly approaching to form the possible methylation pathway. The proposed methylation mechanism of PA catalyzed by COMT helps to develop the therapeutic target for hypertension disease.

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