Comprehensive and quantitative molecular docking analysis of rhodopsin-retinal interactions

Rhodopsin is a retinal protein and a G-protein-coupled receptor that is critical for vertebrate vision. Extensive crystallization efforts of rhodopsin since the publication of its first structure in 2000 have generated 66 entries in the Protein Data Bank of different conformational states of rhodopsin with and without its binding partners arrestin, rhodopsin kinase, and the G-protein, transducin. This provides us with an opportunity to quantify the interactions of retinal with rhodopsin in different conformations at a large scale. We created a database of all bovine rhodopsin structures and classified them into 17 dark-state rhodopsin, 24 opsin, 19 meta-rhodopsin II (meta-II), and six other photo-intermediate (lumi and batho) structures. Across these groups, we also identified 21 entries containing the N2C/D282C substitution mutation that stabilizes the structure. In addition, there are eight meta-II structures with G-protein, four rhodopsins with arrestin (three meta-II) and one opsin with arrestin, four meta-II with kinase, and 10 opsins with transducin. Then, we quantified the binding of retinal to these structures using DiffDock and GNINA minimized affinity analysis and compared the docking of 11-cis-retinal and all-trans-retinal with all conformation and co-complex cases. As expected, meta-II structures tend to bind better to all-trans-retinal, whereas dark structures bind better to 11-cis retinal conformations. However, we also find that the flexibility of the binding pocket in the photo-intermediate states lumi- and batho-rhodopsin enables these conformations to dock with higher affinity to both retinal chromophores. For opsin and active forms with bound proteins, the retinal's binding affinity weakens on average, even though it adopts conformations similar to the canonical inactive and active states, respectively. These results provide a novel, quantitative perspective into the rhodopsin activation process.