G Protein-coupled receptor-bioligand interactions modeled in a phospholipid bilayer

Abstract

ABSTRACT:The arginine vasopressin AVP V2 receptor V2R , a member of the G Ž . protein-coupled receptor GPCR superfamily, mediates the regulation of renal water absorption whose disorders cause nephrogenic diabetes insipidus. A complete molecular Ž . model of V2R embedded in a fully hydrated dimyristoylphosphatidylcholine DMPC bilayer was developed. Both free and AVP-bound states of V2R were studied. An initial V2R was built using a rule-based automated method for GPCR modeling, implementing both the low-resolution structure of bovine rhodopsin and the multisequence analysis of the GPCR superfamily. The loops were added using homology modeling as implemented in SYBYL. The docking site of AVP was selected and justified upon consideration of ligand᎐receptor interactions versus structure᎐activity data. The model was initially relaxed using constrained simulated annealing in vacuo. Subsequently, it was placed in the relaxed fully hydrated DMPC bilayer and submitted to ;1.5 ns molecular dynamics Ž . using the AMBER 4.1 package upon constant number᎐pressure᎐temperature NPT conditions on parallel computers: Cray T3E andror IBM SP2. Physical properties of the system were evaluated and compared with a pure hydrated DMPC bilayer. The receptor᎐ligand interactions, solvation interactions, individual lipid᎐protein interactions, and fluctuations of the protein, the lipid, and water were analyzed in detail. Receptor residues likely to be involved in the ligand binding were selected. As expected, the membrane-spanning helices of the protein fluctuate less than do the peripheral loops. TheCorrespondence to: J. Ciarkowski.

Conformational solution studies of [Sar7]desamino‐ and [MeAla7]desamino‐ vasopressin analogues using NMR spectroscopy

“…The same β-turns were observed in the crystal structure of pressinoic acid [18]. Recently, models of AVP complexed to its V 1a and V 2 receptors were created using molecular modelling [19][20][21]. According to this model the pressin ring interacts with helices of the receptor and with extracellular loops while the C-terminal sticks out of the receptor and possesses a lot of freedom.…”

“…The molecular interaction models for AVP-V 1a (pressor) receptor, V 1aR [18] and for AVP-V 2 (antidiuretic) receptor, V 2R [20,21] have been proposed and described. Despite being quite speculative and different in detail, they have a few things in common.…”

Molecular dynamics simulation studies of lipid bilayer systems.

“…In one, a vasopressin (AVP) molecule was docked to V2R, and the other one contained an "empty" receptor, whose vasopressin binding site was filled with 10 water molecules. A MD simulation was carried out for both systems for 3 ns (Czaplewski et al, 1999a;1999b). Fig.…”