Simulated (Un)Binding of Arachidonic Acid in the Cyclooxygenase site of Prostaglandin H2 Synthase-1

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Abstract
Molecular dynamics simulations with external forces are employed to study the unbinding and binding of arachidonic acid (AA) in the cyclooxygenase (COX) site of prostaglandin H2 synthase-1. Simulations with AA inside the COX binding channel reveal sequences of concerted bond rotations in the fatty acid alkyl chain which obviate the need for gross conformational changes in the protein and substrate during unbinding and binding. The all-cis structure of AA, with double bonds separated by two single bonds, facilitates easy access to the COX channel and correct positioning inside the active site for the COX chemistry to occur. Two derivatives of AA, one with a cis double bond changed to a trans configuration and the other with a double bond reduced to a single bond, are also studied. In both cases the concertedness of bond rotations in the fatty acid chain is diminished and larger forces are required to move the fatty acid inside the COX channel. Important motions of residues near the mouth of the COX channel are found and analyzed. In particular, a conformational “switch” involving Arg83, Glu524 and Arg120 is seen to mediate the movement of the substrate from the membrane to the channel.