title: Understanding rhodopsin mutations linked to the retinitis pigmentosa disease: a QM/MM and DFT/MRCI study.
abstract: Retinitis pigmentosa (RP) is a pathological condition associated with blindness due to progressive retinal degeneration. RP-linked mutations lead to changes at the retinal binding pocket and in the absorption spectra. Here, we evaluate the geometries, electronic effects, and vertical excitation energies in the dark state of mutated human rhodopsins carrying the abnormal substitutions M207R or S186W at the retinal binding pocket. Two models are used, the solvated protein and the protein in a solvated POPC lipid bilayer. We apply homology modeling, classical molecular dynamics simulations, density functional theory (DFT), and quantum mechanical/molecular mechanical (QM/MM) methods. Our results for the wild type bovine and human rhodopsins, used as a reference, are in good agreement with experiment. For the mutants, we find less twisted QM/MM ground-state chromophore geometries around the C(11)-C(12) double bond and substantial blue shifts in the lowest vertical DFT excitation energies. An analysis of the QM energies shows that the chromophore-counterion region is less stable in the mutants compared to the wild type, consistent with recent protein folding studies. The influence of the mutations near the chromophore is discussed in detail to gain more insight into the properties of these mutants. The spectral tuning is mainly associated with counterion effects and structural features of the retinal chain in the case of the hM207R mutant, and with the presence of a neutral chromophore with deprotonated Lys296 in the case of the hS186W mutant.
authors: Departamento de Bioquímica, Instituto de Ciencias Básicas y Preclínicas Victoria de Girón, 11600 Havana City, Cuba.
authors: Erix Wiliam
authors: EW
authors: Hernández-Rodríguez
authors: Elsa
authors: E
authors: Sánchez-García
authors: Rachel
authors: R
authors: Crespo-Otero
authors: Ana Lilian
authors: AL
authors: Montero-Alejo
authors: Luis Alberto
authors: LA
authors: Montero
authors: Walter
authors: W
authors: Thiel
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D011487:Protein Conformation; D011789:Quantum Theory; D012172:Retinaldehyde / Q000737:chemistry / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D012243:Rhodopsin; D012172:Retinaldehyde