The monomeric protein catechol O-methyltransferase (COMT) of rat liver is one of a number of methyl, from AdoMet, transferring enzymes that share a common catalytic domain. As a representative enzyme, COMT has been chosen for molecular dynamic (MD) simulation studies in order to ascertain if there are correlated motions in the ES complex that would be useful in decreasing the energy of activation for the S(N)2 methyl transfer reaction. Such correlative motions have been found and are discussed; The MD trajectory can also provide insight into the observed preference of meta-O-methylation over para-O-methylation for ionic substrates such as dopamine and norepinephrine. The catechol ring has a tilt of approximately 30 compared to that of the X-ray structure. This directs any substituent at the 5-position of the catecholate ring; which is para to the O-methylation site, into a hydrophobic pocket formed by Trp38 and Tyr200. This pocket accommodates hydrophobic substituents such that para-O-methylation is favored. Polar substituents are repelled by this hydrophobic pocket making meta-O-methylation favorable.