| 1. |
- Saura, Patricia, et al.
(författare)
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Electric fields control water-gated proton transfer in cytochrome c oxidase
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:38
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Tidskriftsartikel (refereegranskat)abstract
- Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/ molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme a, leads to dissociation of an arginine (Arg438)–heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å-1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, “chemical,” proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.
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| 2. |
- Alcalde, J., et al.
(författare)
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3-D reflection seismic imaging of the Hontomin structure in the Basque-Cantabrian Basin (Spain)
- 2013
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Ingår i: Solid Earth. - : Copernicus GmbH. - 1869-9510 .- 1869-9529. ; 4:2, s. 481-496
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Tidskriftsartikel (refereegranskat)abstract
- The Basque-Cantabrian Basin of the northern Iberia Peninsula constitutes a unique example of a major deformation system, featuring a dome structure developed by extensional tectonics followed by compressional reactivation. The occurrence of natural resources in the area and the possibility of establishing a geological storage site for carbon dioxide motivated the acquisition of a 3-D seismic reflection survey in 2010, centered on the Jurassic Hontomin dome. The objectives of this survey were to obtain a geological model of the overall structure and to establish a baseline model for a possible geological CO2 storage site. The 36 km(2) survey included approximately 5000 mixed (Vibroseis and explosives) source points recorded with a 25 m inline source and receiver spacing. The target reservoir is a saline aquifer, at approximately 1450 m depth, encased and sealed by carbonate formations. Acquisition and processing parameters were influenced by the rough topography and relatively complex geology. A strong near-surface velocity inversion is evident in the data, affecting the quality of the data. The resulting 3-D image provides constraints on the key features of the geologic model. The Hontom n structure is interpreted to consist of an approximately 10(7) m(2) large elongated dome with two major (W-E and NW-SE) striking faults bounding it. Preliminary capacity estimates indicate that about 1.2 Gt of CO2 can be stored in the target reservoir.
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| 3. |
- Bohlin, Margareta, 1970-, et al.
(författare)
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Riskdiskurser i kvällspressen
- 2014. - 1
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Ingår i: Att förstå ungdomars identitetsskapande. - Stockholm : Liber. - 9789147098330 ; , s. 166-187
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Kapitlet fokuserar på vanligt förekommande sätt att beskriva risker i olika medier.
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| 4. |
- Di Trani, Justin M., et al.
(författare)
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Structural basis of mammalian complex IV inhibition by steroids
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:30
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial electron transport chain maintains the proton motive force that powers adenosine triphosphate (ATP) synthesis. The energy for this process comes from oxidation of reduced nicotinamide adenine dinucleotide (NADH) and succinate, with the electrons from this oxidation passed via intermediate carriers to oxygen. Complex IV (CIV), the terminal oxidase, transfers electrons from the intermediate electron carrier cytochrome c to oxygen, contributing to the proton motive force in the process. Within CIV, protons move through the K and D pathways during turnover. The former is responsible for transferring two protons to the enzyme’s catalytic site upon its reduction, where they eventually combine with oxygen and electrons to form water. CIV is the main site for respiratory regulation, and although previous studies showed that steroid binding can regulate CIV activity, little is known about how this regulation occurs. Here, we characterize the interaction between CIV and steroids using a combination of kinetic experiments, structure determination, and molecular simulations. We show that molecules with a sterol moiety, such as glyco-diosgenin and cholesteryl hemisuccinate, reversibly inhibit CIV. Flash photolysis experiments probing the rapid equilibration of electrons within CIV demonstrate that binding of these molecules inhibits proton uptake through the K pathway. Single particle cryogenic electron microscopy (cryo-EM) of CIV with glyco-diosgenin reveals a previously undescribed steroid binding site adjacent to the K pathway, and molecular simulations suggest that the steroid binding modulates the conformational dynamics of key residues and proton transfer kinetics within this pathway. The binding pose of the sterol group sheds light on possible structural gating mechanisms in the CIV catalytic cycle.
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| 5. |
- Pérez-Perarnau, Alba, et al.
(författare)
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A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 53:38, s. 10150-10154
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Tidskriftsartikel (refereegranskat)abstract
- A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro-apoptotic activity was evaluated. With an EC50 in the low micromolar range, these compounds proved to be potent inducers of apoptosis in a broad spectrum of tumor cell lines, regardless of the functional status of p53. Fast structure-activity relationship studies allowed the preparation of the strongest apoptosis-inducing candidate. Using a high performance affinity purification approach, we identified prohibitins 1 and 2, key proteins involved in the maintenance of cell viability, as the targets for these compounds.
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| 6. |
- Röpke, Michael, et al.
(författare)
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Deactivation blocks proton pathways in the mitochondrial complex I
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:29
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Tidskriftsartikel (refereegranskat)abstract
- Cellular respiration is powered by membrane-bound redox enzymes that convert chemical energy into an electrochemical proton gradient and drive the energy metabolism. By combining large-scale classical and quantum mechanical simulations with cryo-electron microscopy data, we resolve here molecular details of conformational changes linked to proton pumping in the mammalian complex I. Our data suggest that complex I deactivation blocks water-mediated proton transfer between a membrane bound quinone site and proton-pumping modules, decoupling the energy-transduction machinery. We identify a putative gating region at the interface between membrane domain subunits ND1 and ND3/ND4L/ND6 that modulates the proton transfer by conformational changes in transmembrane helices and bulky residues. The region is perturbed by mutations linked to human mitochondrial disorders and is suggested to also undergo conformational changes during catalysis of simpler complex I variants that lack the "active"-to-"deactive" transition. Our findings suggest that conformational changes in transmembrane helices modulate the proton transfer dynamics by wetting/dewetting transitions and provide important functional insight into the mammalian respiratory complex I.
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| 7. |
- Röpke, Michael, et al.
(författare)
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Functional Water Wires Catalyze Long-Range Proton Pumping in the Mammalian Respiratory Complex I
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:52, s. 21758-21766
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Tidskriftsartikel (refereegranskat)abstract
- The respiratory complex I is a gigantic (1 MDa) redox-driven proton pump that reduces the ubiquinone pool and generates proton motive force to power ATP synthesis in mitochondria. Despite resolved molecular structures and biochemical characterization of the enzyme from multiple organisms, its long-range (similar to 300 A) proton-coupled electron transfer (PCET) mechanism remains unsolved. We employ here microsecond molecular dynamics simulations to probe the dynamics of the mammalian complex I in combination with hybrid quantum/classical (QM/MM) free energy calculations to explore how proton pumping reactions are triggered within its 200 A wide membrane domain. Our simulations predict extensive hydration dynamics of the antiporter-like subunits in complex I that enable lateral proton transfer reactions on a microsecond time scale. We further show how the coupling between conserved ion pairs and charged residues modulate the proton transfer dynamics, and how transmembrane helices and gating residues control the hydration process. Our findings suggest that the mammalian complex I pumps protons by tightly linked conformational and electrostatic coupling principles.
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