Large-scale molecular dynamics of a G protein-coupled receptor, the human 5-HT4 serotonin receptor, in a lipid bilayer

The serotonin, h5-HT4 receptor is a G protein-coupled receptor (GPCR) known to be involved in a variety of pathological disorders such as irritable bowel syndrome, cardiac atrial arrhythmia and memory deficits. Recent studies have also underlined its potential role in Alzheimer's disease. We present here the results of molecular dynamics simulations of h5-HT4 receptor binding a non-peptide antagonist ligand in a realistic membrane environment. The GPCR-bound ligand model built in vacuo using homology modelling of bovine rhodopsin and several experimental constraints [L. Rivail, et al., New insights into the human 5-HT4 receptor binding site: exploration of a hydrophobic pocket, Br. J. Pharmacol. 143(3) (2004) 361-370] was relaxed during 10 ns of constant pressure and constant temperature simulation. The results show that the receptor model is stable and that the key interactions formed with the ligand and identified experimentally are conserved. The simulations further reveal that several water molecules migrate from the extracellular milieu toward the putative hydrophobic pocket [L. Rivail, et al., New insights into the human 5-HT4 receptor binding site: exploration of a hydrophobic pocket, Br. J. Pharmacol. 143(3) (2004) 361-370; R. Bureau, et al., Molecular design based on 3D pharmacophore. Application to 5-HT4, J. Chem. Inform. Comput. Sci. (2001) A-F; M.L. Lopez-Rodriguez, et al., Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites. J. Comput. Aided Mol. Des. 11(6) (1997) 589-599] accommodating the ligand, and form a network of interactions with the receptor, hence underlining the limitations of the in vacuo construct. The refined three-dimensional model of the receptor can now be used for docking studies of other ligands, thereby helping the rational design of new drugs for h5-HT4.