Computational studies on the human GnRH-I and the GnRH-receptor

Abstract

Gonadotropin-releasing hormone receptor (GnRH-R), which is a Class A G-protein coupled receptor (GPCR), has a vital role in the regulation of sex hormones. The receptor also has a prominent role in diseases, with examples being reproductive cancers and non-reproductive cancers like glioblastoma. Gonadotropin-releasing hormone (GnRH) agonists have been proven to combat cell proliferation in cancers.

Therefore, studies on how GnRH binds to GnRH-R using computational methods are valuable for further investigation of the GnRH-R activation. The aim was to study the activation mechanism of GnRH-R, in addition to discover how an active model of GnRH-R in complex with GnRH would conformationally change using the computational methods docking and molecular dynamics (MD).

GnRH was docked into a published X-ray crystal structure of GnRH-R and a GnRH-R homology model using Glide® ligand docking and induced fit docking (IFD), this was to study ligand poses and the ligand binding mode. Homology modeling through Prime® was done in order to generate an active structure that was different from the crystal structure, which was inactive. MD simulations were executed in Desmond® to study the ligand binding mode further along with conformational changes.

The results from the docking indicated that GnRH made some known interactions with protein residues in the binding pocket of GnRH-R. However, the ligand did not fully occupy the orthosteric site, and specific residues were sticking out of the binding pocket. MD simulations highlighted differences between the X-ray crystal structure (inactive) and the homology model (active). At the end of the MD simulation, the homology model attained a conformation where transmembrane helices were reminiscent of an active GPCR structure. The crystal structure did not undergo any great conformational change during the MD simulation.