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Electronic and Spatial Characteristics of the Retinylidene Chromophore of Rhodopsin

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Electronic and Spatial Characteristics of the Retinylidene Chromophore of Rhodopsin Electronic and spatial characteristics of the retinylidene chromophore in rhodopsin Verhoeven, M.A. Citation Verhoeven, M. A. (2005, November 15). Electronic and spatial characteristics of the retinylidene chromophore in rhodopsin. Leiden Institute of Chemistry, Biophysical Organic Chemistry/Solid-state NMR, Faculty of Science, Leiden University. Retrieved from https://hdl.handle.net/1887/12041 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral thesis in the License: Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/12041 Note: To cite this publication please use the final published version (if applicable). Electronic and Spatial Characteristics of the Retinylidene Chromophore of Rhodopsin PROEFSCHRIFT ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus Dr. D.D. Breimer, hoogleraar in de faculteit der Wiskunde en Natuurwetenschappen en die der Geneeskunde, volgens besluit van het College voor Promoties te verdedigen op dinsdag 15 november 2005 klokke 14.15 uur door Michiel Adriaan VERHOEVEN geboren te Malden in 1972 Promotiecommissie Promotores: Prof. dr. H.J.M. de Groot Prof. dr. W.J. de Grip Referent: Prof. dr. J. Reedijk Overige leden: Prof. dr. L.W. Jenneskens Prof. dr. A.P. IJzerman Prof. dr. H.S. Overkleeft Prof. dr. J. Brouwer Table of contents CHAPTER 1 GENERAL INTRODUCTION .......................................................................................................9 1.1 INTRODUCTION .....................................................................................................................10 1.2 RHODOPSIN..........................................................................................................................10 1.3 THE STRUCTURE OF THE VERTEBRATE EYE, RODS AND CONES ...............................................13 1.4 G-PROTEIN COUPLED RECEPTORS.........................................................................................14 1.5 THE RATE AND EFFICIENCY OF THE PHOTOREACTION OF RHODOPSIN......................................16 1.6 AIM AND SCOPE OF THIS THESIS ............................................................................................20 CHAPTER 2 NOVEL EFFICIENT SYNTHESIS ROUTES TO 11-METHYL RETINAL ISOMERS.................25 2.1 ABSTRACT.............................................................................................................................26 2.2 INTRODUCTION.......................................................................................................................26 2.3 RESULTS ...............................................................................................................................27 2.4 DISCUSSION...........................................................................................................................29 2.5 CONCLUSION .........................................................................................................................31 2.6 EXPERIMENTAL DETAILS ........................................................................................................32 CHAPTER 3 THE ELECTRONIC STRUCTURE OF THE RETINYLIDENE CHROMOPHORE IN RHODOPSIN..............................................................................................................................41 3.1 ABSTRACT .............................................................................................................................42 3.2 INTRODUCTION .......................................................................................................................42 3.3 MATERIALS AND METHODS......................................................................................................43 3.4 RESULTS................................................................................................................................46 3.5 DISCUSSION ...........................................................................................................................49 3.6 CONCLUSIONS .......................................................................................................................56 CHAPTER 4 METHYL SUBSTITUENTS AT THE 11- OR 12-POSITION OF RETINAL PROFOUNDLY AFFECT PHOTOCHEMISTRY AND FUNCTION OF RHODOPSIN .........................................59 4.1 ABSTRACT.............................................................................................................................60 4.2 INTRODUCTION.......................................................................................................................60 4.3 MATERIALS AND METHODS.....................................................................................................61 4.3.1 SYNTHESIS ............................................................................................................................61 4.3.2 GENERATION OF RHODOPSIN ANALOGUES ...................................................................................63 4.3.3 SPECTRAL ANALYSIS OF THE RHODOPSIN DERIVATIVES AND PHOTOINTERMEDIATE FORMATION .............64 4.3.4 PHOTOSENSITIVITY OF PIGMENTS ...............................................................................................64 4.3.5 FTIR SPECTROSCOPY..............................................................................................................65 4.3.6 SIGNAL TRANSDUCTION ...........................................................................................................66 4.4 RESULTS AND DISCUSSION.....................................................................................................66 4.4.1 11-METHYL RHODOPSIN ...........................................................................................................67 4.4.2 12-METHYL RHODOPSIN ...........................................................................................................75 4.4.3 11-METHYL-13-DESMETHYL RHODOPSIN AND ISORHODOPSIN ..........................................................79 4.5 CONCLUSION .........................................................................................................................83 CHAPTER 5 GENERAL DISCUSSION AND OUTLOOK...............................................................................87 5.1 INTRODUCTION.......................................................................................................................88 5.2 SYNTHESIS OF RETINAL DERIVATIVES......................................................................................88 5.3 ANALYSIS OF THE RHODOPSIN ANALOGUES ............................................................................90 5.4 ELECTRONIC STRUCTURE OF THE RETINYLIDENE IN RHODOPSIN...............................................92 LIST OF ABBREVIATIONS.......................................................................................................96 SUMMARY.................................................................................................................................98 SAMENVATTING.....................................................................................................................101 LIST OF PUBLICATIONS........................................................................................................104 CURRICULUM VITAE .............................................................................................................107 Chapter 1 General Introduction 9 Chapter 1 1.1 INTRODUCTION Rhodopsin is the protein in the retina of vertebrates responsible for dim light or black and white vision. The protein functions as a light-driven molecular switch that initiates a cascade of biochemical reactions, ultimately leading to a nerve pulse to the brain. Approximately seventy years ago George Wald discovered that retinas from frog eyes bleached from purple to orange releasing a compound resembling vitamin A.1 To explain the chemistry of vision, he proposed a cycle in which the vitamin A derivative binds to a protein in the dark and was released in contact with light. In 1952 Wald and his co-workers demonstrated that it is in fact 11-Z retinal that binds to opsin, the apoprotein of rhodopsin.2 At the end of the 1960s it was established that light isomerises 11-Z retinal that is bound to the protein and is released as all-E retinal.3 A wealth of information is available on the biological, chemical, physical aspects that are related to the processes of vision. In this chapter the details of the machinery of the process of vision are introduced, going from the level of the molecular switch to its function at the macroscopic level in the eye. In addition, the ultrafast and efficient isomerisation properties of the retinylidene chromophore are discussed, followed by the scope and outline of this thesis. 1.2 RHODOPSIN Rhodopsin is a 40 kDa integral membrane protein that consists of 348 amino acid residues. Recently, the X-ray structure of rhodopsin was published.4 A schematic representation of this structure is depicted in Figure 1.1. Like many proteins in the class of G-protein coupled receptors (GPCRs), it has 7-transmembrane α-helices. An eighth helix is found parallel to the membrane at the intradiscal interface of the membrane.4 For its function the rhodopsin protein relies on the co-factor retinal (vitamin-A aldehyde) that is covalently bound to the ε−amino group of lysine residue 296 via a protonated Schiff base (PSB) linkage.5,6 In the dark the retinylidene chromophore has the
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