caa a22 4500 467938636 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060801xx s 000 0 eng 10.1007/s10822-006-9068-9 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9068-9 Cannabinoid CB1 receptor recognition of endocannabinoids via the lipid bilayer: molecular dynamics simulations of CB1 transmembrane helix 6 and anandamide in a phospholipid bilayer [Elektronische Daten] [Diane Lynch, Patricia Reggio] The phospholipid bilayer plays a central role in the lifecycle of the endogenous cannabinoid, N-arachidonoylethanolamine (anandamide, AEA). Therefore, the orientation and location of AEA in the phospholipid bilayer with respect to key membrane associated proteins, is a central issue in understanding the mechanism of endocannabinoid signaling. In this paper, we report a test of the hypothesis that a βXXβ motif (formed by beta branching amino acids, V6.43 and I6.46) on the lipid face of the cannabinoid CB1 receptor in its inactive state may serve as an initial CB1 interaction site for AEA. Eight 6ns NAMD2 molecular dynamics simulations of AEA were conducted in a model system composed of CB1 transmembrane helix 6 (TMH6) in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer. In addition, eight 6ns NAMD2 molecular dynamics simulations of a low CB1 affinity (20:2, n−6) analog of AEA were conducted in the same model system. AEA was found to exhibit a higher incidence of V6.43/I6.46 groove insertion than did the (20:2, n−6) analog. In certain cases, AEA established a high energy of interaction with TMH6 by first associating with the V6.43/I6.46 groove and then molding itself to the lipid face of TMH6 to establish a hydrogen bonding interaction with the exposed backbone carbonyl of P6.50. Based upon these results, we propose that the formation of this hydrogen bonded AEA/TMH6 complex may be the initial step in CB1 recognition of AEA in the lipid bilayer. Springer Science+Business Media, LLC, 2006 Anandamide nationallicence Bilayer nationallicence Cannabinoid nationallicence CB1 nationallicence Endocannabinoid nationallicence GPCR nationallicence Lipid nationallicence Molecular dynamics nationallicence Groove nationallicence AEA : N-arachidonoylethanolamine nationallicence CB1 : Cannabinoid Receptor Type 1 nationallicence CM : Conformational Memories nationallicence FAAH : fatty acid amide hydrolase nationallicence GPCR : G protein-coupled receptor nationallicence Rho : Rhodopsin nationallicence Lynch Diane Center for Drug Design, Department of Chemistry and Biochemistry, University of North Carolina Greensboro, 435 New Science Building, P.O. Box 26170, 27402-6170, Greensboro, NC, USA aut Reggio Patricia Center for Drug Design, Department of Chemistry and Biochemistry, University of North Carolina Greensboro, 435 New Science Building, P.O. Box 26170, 27402-6170, Greensboro, NC, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 495-509 0920-654X 20:7-8<495 2006 20 10822 https://doi.org/10.1007/s10822-006-9068-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9068-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lynch Diane Center for Drug Design, Department of Chemistry and Biochemistry, University of North Carolina Greensboro, 435 New Science Building, P.O. Box 26170, 27402-6170, Greensboro, NC, USA aut NATIONALLICENCE 700 1- Reggio Patricia Center for Drug Design, Department of Chemistry and Biochemistry, University of North Carolina Greensboro, 435 New Science Building, P.O. Box 26170, 27402-6170, Greensboro, NC, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 495-509 0920-654X 20:7-8<495 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer