Molecular Dynamics Analysis of FAAH complexed with Anandamide

Fatty Acid Amide Hydrolase (FAAH) is a very interesting serinehydrolase that promotes the hydrolysis of both amides and esters, such as theendogenous cannabinoid anandamide or N-arachidonoyl ethanolamine (AEA), andthe sleep-inducing lipid oleamide. The therapeutic potential from the pharmacologicalmodulation of this enzyme is vast, including relevant neurological andinflammatory disorders. Different computational approaches have fallen upon thecharacterization of the oleamide-FAAH monomer complex. With this study, wepropose a description of both the dimeric and monomeric FAAH complexes withthe substrate anandamide, in order to look for relevant interactions in the active-siteand differences in the monomer and dimer incorporation approaches. The studyinvolves a comparative analysis of several important molecular aspects for whichare vital not only motion but also the conformational sampling of both enzyme andsubstrate as well as their interaction, with the inclusion of solvent. This workcomprises aflexibility analysis of FAAH through Root Mean Square Fluctuation(RMSF),SolventAccessibleSurfaceAccessibleArea(SASA)measurementsonthesubstrate andenzyme,Radial DistributionFunctions(RDFs)ofthewatermoleculeshydrating anandamide, as well as a study on significant hydrogen bonds betweenthe active-site residues and the substrate. The results highlight meaningful interactingresiduesoftheFAAHactive-sitewiththeAEAsubstrate,andtheimportanceof considering the dimeric complex whenflexibility effects are relevant.