Structure-Function Relationship of Retinal Proteins.

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Presentation transcript:

Structure-Function Relationship of Retinal Proteins

Retinal proteins or rhodopsins belong to the superfamily of seven- transmembrane helical (7TM) proteins. Seven helices, with N-terminus on the extracellular side and C-terminus on the cytoplasmic side of the membrane (not necessarily G-protein coupled) A B C D E F G Structure of Retinal Proteins GPCRs

Retinal Proteins -- Rhodopsins Covalently linked to a lysine Usually protonated Schiff base all-trans and 11-cis isomers Chromophore

 The simplest ion pump in biology  The best characterized membrane protein  The simplest photosynthetic center  Technological applications in molecular electronics Bacteriorhodopsin -- bR  The first membrane protein with a known atomic-detail 3D structures

Halobacterium Salinarum The Purple Membrane H+H+ h [H + ] ADP ATP Cytoplasmic sideExtracellular side ATP Synthase h bR role in Bioenergetics Light Proton Gradient

Cytoplasmic side Extracellular side Schematic proton path in bacteriorhodopsin Transmambrane helices H+H+ H+H+

Active Channels Need a ‘Switch’ Mechanism H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ h H+H+ H+H+ What is the switch in bR? How does it work?

Photocycle of bR Photo-induced All intermediates are trapped in low temperature and have been characterized by vibrational and absorption spectroscopy. 3 ps  s 40  s 5 ms

No membrane protein has been studied as extensively as bR Photo-induced 3 ps  s 40  s 5 ms All intermediates have also been characterized by X-ray crystallography!

Cytoplasmic side Extracellular side Schematic proton path in bacteriorhodopsin Transmambrane helices

cytoplasmic extracellular H+H+ light driven proton pump + H D85-COO HOOC-E204 HOOC-D96 N + H D85-COO HOOC-E204 HOOC-D96 N K216 bR 568 K H D85-COO HOOC-E204 HOOC-D96 N K216 D85-COOH OOC-E204 HOOC-D96 N K216 L 543 M H D85-COOH OOC-E204 OOC-D96 N K216 N H D85-COOH OOC-E204 HOOC-D96 N K216 O 645 3ps  s 40  s 5ms BR’s Photocycle

+ H D85-COO HOOC-E204 HOOC-D96 N + H D85-COO HOOC-E204 HOOC-D96 N K216 bR 568 K H D85-COO HOOC-E204 HOOC-D96 N K216 D85-COOH OOC-E204 HOOC-D96 N K216 L 543 M H D85-COOH OOC-E204 OOC-D96 N K216 N H D85-COOH OOC-E204 HOOC-D96 N K216 O 645 3ps  s 40  s 5ms Kuhlbarandt, Nature, 406,569 (2000) Conformational Change of Helices BR’s Photocycle

 bR in the purple membrane Modeling of the protein in lipid bilayers  Chromophore Analysis of the structure Calculation of excited state dynamics  Protein Chromophore-protein interaction QM-MM calculations MD simulation of the photocycle Study of bR at three levels

Retinal Schiff base Membrane, covalently bound, chromophore Retinoic Acid Nucleus, receptor site, ligand (no photoactivity) Retinoids Retinal

       The necessity of quantum mechanical treatment of the chromophore: Conjugated  -electronic system, delocalization The effect of protein matrix on the ligand Unconventioanl chemistry QM is expensive – Most of the time, one needs to use models

Proton Affinity: PA= E AH -(E A +E H ) Effect of Conjugation on pK a (Gas Phase Proton Affinity)

Proton Affinity: PA= E AH -(E A +E H ) Effect of the methyl groups on pK a No more room for additional methyl groups on the backbone

h What is the effect of isomerization?

Proton Affinity: PA= E AH -(E A +E H ) cc: B2,B3-di-cis isomerct: B2-s-cis, B3-trans isomer tc: B2-strans, B3-cis isomertt: all-trans isomer. Isomerization State and Proton Affinity Isomerization does not have a strong impact on PA!

h What is the effect of isomerization?

Water Asp 85 Asp 212 Water Counterion: Asp 85 & Asp 212 WATER pK a : ~ max : ~ Opsin shift Retinal binding pocket in bR

Proton Affinity: PA= E AH -(E A +E H ) Effect of the environment on PA

In situ isomerization and pK a

S0S0 S1S1 K BR C 13 =C 14 -transC 13 =C 14 -cis Coupling of electronic excitation and conformational change in bR

h trans cis Ground and Excited State Potential Energy Surfaces of Retinal

Ab Initio QM/MM Excited State MD Simulation QM Quantum mechanical (QM) treatment of the chromophore, and force field (MM) treatment of the embedding protein

Proton Affinity: PA= E AH -(E A +E H ) Low barriers against double bond isomerization Ground state isomerization Isomerization Barriers in retinal

A twisted chromophore is also experimentally reported. X-ray structures of bR report the twisted form of chromophore The twist is found around the terminal double bonds It may influence pK a of the chromophore 165°168° 178° 177°176°177° A twisted chromophore in bR?