Molecular Dynamics Analysis of FAAH
Complexed with Anandamide
Sérgio F. Sousa, João T.S. Coimbra, Pedro A. Fernandes,
Tiziana Marino, Maria J. Ramos and Nino Russo
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.
Keywords Fatty acid amide hydrolase Á Anandamide Á Molecular dynamics
S.F. Sousa Á J.T.S. Coimbra Á P.A. Fernandes Á M.J. Ramos (&)
REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
e-mail: mjramos@fc.up.pt
T. Marino (&) Á N. Russo
Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per
Elaborazioni Parallele e Distribuite-Centro d’Eccellenza MIUR,
Università della Calabria, 87030 Arcavacata di Rende, CS, Italy
e-mail: tmarino@unical.it
© Springer International Publishing Switzerland 2015
M.A.C. Nascimento et al. (eds.), Frontiers in Quantum Methods and Applications
in Chemistry and Physics, Progress in Theoretical Chemistry and Physics 29,
DOI 10.1007/978-3-319-14397-2_7
115
Complexed with Anandamide
Sérgio F. Sousa, João T.S. Coimbra, Pedro A. Fernandes,
Tiziana Marino, Maria J. Ramos and Nino Russo
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.
Keywords Fatty acid amide hydrolase Á Anandamide Á Molecular dynamics
S.F. Sousa Á J.T.S. Coimbra Á P.A. Fernandes Á M.J. Ramos (&)
REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
e-mail: mjramos@fc.up.pt
T. Marino (&) Á N. Russo
Dipartimento di Chimica and Centro di Calcolo ad Alte Prestazioni per
Elaborazioni Parallele e Distribuite-Centro d’Eccellenza MIUR,
Università della Calabria, 87030 Arcavacata di Rende, CS, Italy
e-mail: tmarino@unical.it
© Springer International Publishing Switzerland 2015
M.A.C. Nascimento et al. (eds.), Frontiers in Quantum Methods and Applications
in Chemistry and Physics, Progress in Theoretical Chemistry and Physics 29,
DOI 10.1007/978-3-319-14397-2_7
115