Molecular Dynamics Analysis of FAAH Complexed with Anandamide

Abstract

Fatty Acid Amide Hydrolase (FAAH) is a very interesting serine hydrolase that promotes the hydrolysis of both amides and esters, such as the endogenous cannabinoid anandamide or N-arachidonoyl ethanolamine (AEA), and the sleep-inducing lipid oleamide. The therapeutic potential from the pharmacological modulation of this enzyme is vast, including relevant neurological and inflammatory disorders. Different computational approaches have fallen upon the characterization of the oleamide-FAAH monomer complex. With this study, we propose a description of both the dimeric and monomeric FAAH complexes with the substrate anandamide, in order to look for relevant interactions in the active-site and differences in the monomer and dimer incorporation approaches. The study involves a comparative analysis of several important molecular aspects for which are vital not only motion but also the conformational sampling of both enzyme and substrate as well as their interaction, with the inclusion of solvent. This work comprises a flexibility analysis of FAAH through Root Mean Square Fluctuation (RMSF), Solvent Accessible Surface Accessible Area (SASA) measurements on the substrate and enzyme, Radial Distribution Functions (RDFs) of the water molecules hydrating anandamide, as well as a study on significant hydrogen bonds between the active-site residues and the substrate. The results highlight meaningful interacting residues of the FAAH active-site with the AEA substrate, and the importance of considering the dimeric complex when flexibility effects are relevant.