144
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.
