Structures of the first intermediates of the visual cascade

• Applicant: Professor Dr. Peter Entel (†)
• Subject Area: Physical Chemistry of Molecules, Liquids and Interfaces, Biophysical Chemistry
• Term: from 2002 to 2006
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5469831

Rhodopsin, the photoreceptor for dim light vision in the vertebrate eye, is a so-called G-protein coupled receptor or GPCR. The primary step of the visual cascade of rhodopsin is the isomerization from cis to trans of the C11=C12 double bond of retinal, the chromophore of rhodopsin, to form the bathorhodopsin intermediate. Bathorhodopsin is transformed in several steps into metarhodopsin II which couples with the G-protein and triggers the visual cascade. Rhodopsin is the first GPCR of which the X-ray structure has been solved. This structure is a first step for understanding the visual process at the molecular level. However, the 2.8 Å resolution is not sufficient for a detailed analysis of the chromophore and its interaction with the protein environment. Fine points of the chromophore geometry, which are essential for the selectivity and reactivity of the receptor and the subsequent interconversions, remain in doubt. Subject of the proposal is the calculation of realistic models of rhodopsin and of bathorhodopsin based on the experimental X-ray structure. We will use rigorous quantum-chemistry for the chromophore, density functional-based tight-binding (DFTB) for the chromophore including the binding pocket, and combined quantum mechanical/molecular mechanics for the whole protein. The focus, for rhodopsin, will be on the tight fit between the chromophore and protein, which stabilizes the ground state and sets it up for photo-isomerization. For bathorhodopsin, we will concentrate on the steric non-fit of the chromophore after photoexcitation, how its enforced geometry affects the binding pocket and prepares the whole protein on its path towards G-protein activation.

• DFG Programme: Research Units
• Subproject of: FOR 490: Molecular Mechanisms of Retinal Protein Action: A Combination of Theoretical Approaches
• Participating Person: Professor Dr. Volker Buß