QM/MM Investigation of the Primary Photochemical Event in Vision

The energy-storage, the electronic-excitation energy-shift and the molecular rearrangements due to the primary photochemical event in rhodopsin are investigated using QM/MM(MO:MM) hybrid methods in conjunction with high-resolution structural data of bovine visual rhodopsin. It is assumed that the primary process involves 11-cis/all-trans isomerization of the retinyl chromophore within a time scale much shorter than the protein relaxation time. The analysis of the molecular structures, obtained after electronicand partial nuclear-relaxation along the 11-cis/all-transisomerization path, reveals the detailed molecular rearrangements of the retinyl chromophore in the rhodopsin binding pocket; the preferential sense of rotation of the φ(C11-C12) dihedral angle; and the detailed chromophore-protein interactions responsible for the energy-storage mechanism and the initial rotational torque. It is revealed that the φ(C11-C12) dihedral angle changes from -10° in the 11-cis isomer to -165° in the all-trans isomer, with a preferential sense of rotation determined by the steric Van der Waals interactions between Ala117 and the polyene chain at the C13 position. The polyene chain of the all-trans isomer is significantly bent and twisted due to space constraints in the binding pocket, including out-of-the-plane distortions larger than 15° in the dihedral angles of the C7-C8, C9-C10, C12-C13, C14-C15 and C15-NH(+) chromophore bonds. It is shown that the energy-storage computed at the ONIOM-EE (B3LYP/6-31G*:Amber) level of theory is 29 kcal/mol, in very good agreement with experimental measurements (32—35 ± 3 kcal/mol). It is predicted that 40 % of the energy stored is strain energy, due to the steric constraints of the all-trans isomer in the rhodopsin binding pocket. The remaining 60 % is electrostatic energy due to stretching of the salt-bridge between the protonated Schiff-base and the Glu113 counterion. The analysis of the salt-bridge stretching mechanism indicates that the underlying process involves solely torsion of the polyene chain. The consequent reorientation of the polarized bonds C15-H and N-H displaces the net positive charge at the Schiff-linkage, relative to the Glu113 counterion, without displacing the linkage itself, or inducing a redistribution of atomic charges within the chromophore. It is demonstrated that a hydrogen-bonded water molecule, consistently found by X-ray crystallographic studies, can assist the salt-bridge stretching process by stabilizing the reorientation of the polarized bonds at the Schiff-linkage. Finally, it is shown that the ONIOM-EE (TD-B3LYP/6-31G*//B3LYP/631G*:Amber) level of theory predicts that the S0 → S1 electronic-excitation energy-shift caused by the underlying molecular rearrangements is ∆∆E =3.2 kcal/mol, in quantitative agreement with experimental measurements (3.4 kcal/mol). These results are particularly relevant to the development of a first principles understanding of the structure-function relationship of G-protein-coupled receptors at the detailed molecular level.