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.
Subject(s)
Molecular Dynamics Simulation , Mutation , Retinitis Pigmentosa/genetics , Rhodopsin/chemistry , Rhodopsin/genetics , Animals , Binding Sites , Cattle , Crystallography, X-Ray , Humans , Lipid Bilayers/chemistry , Models, Molecular , Molecular Sequence Data , Molecular Structure , Protein Conformation , Quantum Theory , Retinaldehyde/chemistry , Retinaldehyde/metabolism , Rhodopsin/metabolismABSTRACT
The potential energy surface of the CH(4)...NO van der Waals complexes was explored at the RCCSD(T)/aug-cc-pVTZ level including the full counterpoise correction to the basis set superposition error. The Jahn-Teller distortion of the C(3v) configurations for the CH bonded and CH(3) face complexes was analyzed. From this distortion, two A(') and A(") adiabatic surfaces were considered. The estimated zero point energy of C(s) configurations is above the barrier of the C(3v) ones. Therefore, the CH(3) face complexes are dynamic Jahn-Teller systems. The D(0) (140 cm(-1) for A(") state and 100 cm(-1) for A(')) values obtained are in good agreement with the experimental values (103+/-2 cm(-1)) recently reported.
ABSTRACT
A systematic study of basis set superposition error (BSSE) behavior in H(3)C-H[ellipsis (horizontal)][NO] complexes for both -H...N- and -H...O- orientations were carried out using MP2 and density-functional theory with Pople's [6-31G(d,p),6-311++G(nd,nd), where n=1,2,3, and 6-311++G(3df,3pd)] and Dunning's augmented correlation consistent basis sets [aug-cc-pVXZ (X=D and T)]. Corrected and uncorrected counterpoise potential-energy surfaces (PESs) were explored and differences obtained between them indicate that reliable optimizations of these molecular interactions must be carried out in a PES free of BSSE, even in the case of large basis sets and popularly used functionals such as B3LYP. Although all basis used could be always considered within a margin of approximation for representing molecular orbitals and show important values of BSSE, 6-311++G(2d,2p) basis set shows the best results in uncorrected PES with respect to the corrected ones. B3LYP functional produces erratic results: complexes appear repulsive and the intermolecular distances are always large, evidencing the lack of a correct dispersive forces treatment in the original parameterization. According to the MP2 results, the -H...N- interactions appear as slightly more stable than those of the -H...O- orientation.
