G protein-coupled receptors (GPCRs) are 7-helical transmembrane proteins that comprise the largest superfamily of plasma membrane receptors and are the primary target for pharmaceutical development. Upon ligand binding, the GPCR is capable to catalyze GDP–GTP exchange in heterotrimeric G proteins and regulate the intracellular level of secondary messengers. Rhodopsin, the first protein structure solved by X-ray diffraction, is the primary model for studying GPCRs. As this protein is located at the human rod cells, the visual chromophore ligand (11-cis-retinal) is covalently bound to Lys 296 by a protonated Schiff base. This ligand in the dark state acts as an inverse agonist that is converted by light-induced isomerization to the all-trans agonist, driving the conformational transitions leading to receptor activation. In this mechanism, several intermediates are formed within milliseconds, such as bathorhodopsin, lumirhodopsin, and Meta I and Meta II states. Experimental data have shown significant differences between the opsin (active-like state) and rhodopsin (inactive state). The primary difference in these states is that the opsin structure is obtained after the release of the all-trans-retinal so, thus becoming the apoprotein; while in rhodopsin (the inactive state), the protein is bound to the 11-cis-retinal. These experimental information lead us to hypothesize that the difference in flexibility between rhodopsin and opsin is due to local fluctuations, at atomic level, which may be observable in the molecular dynamics simulations timescale. The structures of rhodopsin and opsin were downloaded from the Protein Data Bank, and placed on a hydrated membrane bilayer at physiological conditions. All atom molecular dynamics simulations were performed for 100 ns. Root Mean Square Deviation (RMSD) of the backbone proteins and Root Mean Square Fluctuation (RMSF) of residues was analyzed and compared with results reported on literature.

Flexibility at different stages of mechanism of activation of the GPCR-prototype agrees with local motions explored by molecular dynamics simulations

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.