How Rhodopsin Tunes the Equilibrium between Protonated and Deprotonated Forms of the Retinal Chromophore

Ursula Röthlisberger, Alicia Solano, Siri Camee van Keulen
2017
Article

Résumé

Rhodopsin is a photoactive G-protein-coupled receptor (GPCR) that converts dim light into a signal for the brain, leading to eyesight. Full activation of this GPCR is achieved after passing through several steps of the protein's photoactivation pathway. Key events of rhodopsin activation are the initial cis-trans photoisomerization of the covalently bound retinal moiety followed by conformational rearrangements and deprotonation of the chromophore's protonated Schiff base (PSB), which ultimately lead to full activation in the meta II state. PSB deprotonation is crucial for achieving full activation of rhodopsin; however, the specific structural rearrangements that have to take place to induce this plc shift are not well understood. Classical molecular dynamics (MD) simulations were employed to identify intermediate states after the cis trans isomerization of rhodopsin's retinal moiety. In order to select the intermediate state in which PSB deprotonation is experimentally known to occur, the validity of the intermediate configurations was checked through an evaluation of the optical properties in comparison with experiment. Subsequently, the selected state was used to investigate the molecular factors that enable PSB deprotonation at body temperature to obtain a better understanding of the difference between the protonated and the deprotonated state of the chromophore. To this end, the deprotonation reaction has been investigated by applying QM/MM MD simulations in combination with thermodynamic integration. The study shows that, compared to the inactive 11-cis-retinal case, trans-retinal rhodopsin is able to undergo PSB deprotonation due to a change in the conformation of the retinal and a consequent alteration in the hydrogen-bond (HB) network in which PSB and the counterion.G1u113 are embedded. Besides the retinal moiety and Glu113, also two water molecules as well as Thr94 and Gly90 that are related to congenital night blindness are part of this essential HB network.

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Ursula Röthlisberger, Alicia Solano, Siri Camee van Keulen
2017
Article

Résumé

Official source

https://infoscience.epfl.ch/record/230207?ln=fr

À propos de ce résultat

Concepts associés (9)

Concepts associés

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Publications associées (14)

Publications associées

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Early Steps of the Intramolecular Signal Transduction in Rhodopsin Explored by Molecular Dynamics Simulations

Leonardo Guidoni, Ursula Röthlisberger

We present mol. dynamics simulations of bovine rhodopsin in a membrane mimetic environment based on the recently refined x-ray structure of the pigment. The interactions between the protonated Schiff base and the protein moiety are explored both with the chromophore in the dark-adapted 11-cis and in the photoisomerized all-trans form. Comparison of simulations with Glu181 in different protonation states strongly suggests that this loop residue located close to the 11-cis bond bears a neg. charge. Restrained mol. dynamics simulations also provide evidence that the protein tightly confines the abs. conformation of the retinal around the C12-C13 bond to a pos. helicity. 11-cis to all-trans isomerization leads to an internally strained chromophore, which relaxes after a few nanoseconds by a switching of the ionone ring to an essentially planar all-trans conformation. This structural transition of the retinal induces in turn significant conformational changes of the protein backbone, esp. in helix VI. Our results suggest a possible mol. mechanism for the early steps of intramol. signal transduction in a prototypical G-protein-coupled receptor. [on SciFinder (R)]

2002

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Characterization of the Dizinc Analogue of the Synthetic Diiron Protein DF1 Using ab Initio and Hybrid Quantum/Classical Molecular Dynamics Simulations

Ursula Röthlisberger

The structural and dynamical properties of the four a-helix bundle Due Ferri 1, which is a generic mimic of diiron proteins, have been explored using d. functional theory (DFT) based and hybrid quantum/classical mol. dynamics (QM/MM) simulations. Four quantum mech. (QM) representations of the active site have been employed in order to systematically assess the role of first and second shell interactions: (a) a 66-atom fragment of the active site comprising only first shell ligands, (b and c) two systems (78 and 86 atoms) contg. different second shell hydrogen bonds, and (d) a 98-atom model including both the first and second shell residues. Two QM/MM partitioning schemes have been explored in order to explicitly consider the role of the whole protein environment: (a) a 54-QM-atom model in which only the first shell ligands are described at the DFT level, while the rest of the protein environment is taken into account at the MM level and (b) a 68-QM-atom model in which the first shell ligands plus a second shell hydrogen bond network is considered at the DFT level. All of the calcns. confirm the highly flexible nature of the carboxylate-bridged binuclear motif and demonstrate the importance of the whole protein environment in stabilizing the hydrogen bond networks that surround the active site. The present QM/MM approach allows for the identification of key factors governing the stability/reactivity of the active site and thus provides unique insights that can be exploited for the future tailoring of new highly selective biomimetic enzymic compds. [on SciFinder (R)]

2003

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A misfolded conformer of the cellular prion protein, denoted as scrapie prion protein, is considered responsible for a variety of fatal neurodegenerative diseases. Both, the function of the protein in its native conformation as well as the factors that trigger the protein misfolding and its mechanism remain as yet open issues. The aim of this thesis is to give a contribution to answering these questions by means of a variety of tools currently available in the computational (bio)chemistry community. The capability of the cellular prion protein isoform to bind metal is supported by controversial evidences and atomistic details of putative binding sites are missing. Based on the NMR structure of the C-terminal part of the cellular isoform, we performed a hybrid quantum/classical (QM/MM) Car-Parrinello molecular dynamics study to identify likely Cu(II) binding sites. By means of a bioinformatics approach, we localized the protein regions with the highest propensity for copper ion binding. The identified candidate structures were subsequently refined via QM/MM simulations and then probed by computing their EPR characteristics. Overall best agreement with the experimental EPR data was observed for a binding site involving H187. The previously characterized prion protein Cu(II)-binding sites were substituted for Mn(II) and Zn(II) and subsequently refined by means of the QM/MM Car-Parrinello approach. As a general conclusion, all the Cu-binding sites lead to stable arrangements upon Mn and Zn substitution with relative minor structural changes even within the ps time scale. The validity of the binding motifs obtained was assessed by means of comparison with a pool of known Mn and Zn binding proteins and common features were found and described. The Zn binding site in proximity of H177 was speculated to act as a protein interface zinc site with a possible direct involvement in the aggregation process. The EPR parameters of the Mn-containing binding sites were also computed. The influence of some environmental factors that can possibly trigger the misfolding event were investigated via classical molecular dynamics simulations. Specifically, protein solution containing a monovalent salt (NaCl) in four different concentrations (0.0, 0.05, 0.1, 0.2 M) were simulated at three different pH (pH 2, 4, 7) in order to highlight structural changes and local weaknesses in the protein native structural motifs. The effects of the ionic strength and pH on the secondary structural elements of the protein were identified and characterized whereas the main topological framework was preserved in all simulations. The energy landscape of the cellular to scrapie isoform misfolding pathway is currently under investigation by means of a parallel tempering (replica exchange) enhanced sampling technique in combination with classical molecular dynamics. The screening of the data collected led to the identification of a pool of prion protein scrapie candidates. A set of new folding motifs were characterized. Preliminary results and plans for future investigations are presented. With the goal of providing a structural model for the minimal misfolded aggregate based on the most likely prion protein scrapie candidates, a protein-protein docking approach was used to generate protofibril models and their structural stability and transformations investigated by means of classical molecular dynamics simulations.

EPFL2006

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EPFL2006