Dynamics of different arachidonic acid orientations bound to prostaglandin endoperoxide synthases

Prostaglandin endoperoxide synthases (PGHSs) catalyze the conversion of arachidonic acid (AA) into prostaglandin endoperoxide H2. This reaction requires a specific orientation of AA within the active site, but an alternative crystallographic binding orientation for AA also exists. Since the origin of this alternative complex, and its potential relevance, have been neglected so far, we have characterized the dynamics of both orientations of AA, bound to PGHS-1 and -2, in order to obtain new insights for designing PGHSs inhibitors. Our results indicate that AA in the alternative orientation seems to be less stable, moving toward Arg120. Such potentially minor orientation of AA can be related to crystallographic complexes of anti-inflammatory agents, pointing to an alternate SAR on PGHSs inhibitors.

Unlike the catalytic orientation, the alternative orientation of AA within PGHSs active site does not maintain its original position during MD simulation, moving toward Arg120.Figure optionsDownload as PowerPoint slideHighlights
► AA may present two orientations within PGHSs: catalytic and alternative.
► The alternative orientation of AA is highly similar to diclofenac orientation.
► AA alternative orientation behaves as a minor population in solution.