| 1. |
- Kriebisch, Brigitte A. K., et al.
(författare)
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Reciprocal Coupling in Chemically Fueled Assembly : A Reaction Cycle Regulates Self-Assembly and Vice Versa
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:49, s. 20837-20844
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Tidskriftsartikel (refereegranskat)abstract
- In biology, self-assembly of proteins and energy-consuming reaction cycles are intricately coupled. For example, tubulin is activated and deactivated for assembly by a guanosine triphosphate (GTP)-driven reaction cycle, and the emerging microtubules catalyze this reaction cycle by changing the microenvironment of the activated tubulin. Recently, synthetic analogs of chemically fueled assemblies have emerged, but examples in which assembly and reaction cycles are reciprocally coupled remain rare. In this work, we report a peptide that can be activated and deactivated for self-assembly. The emerging assemblies change the microenvironment of their building blocks, which consequently accelerate the rates of building block deactivation and reactivation. We quantitatively understand the mechanisms at play, and we are thus able to tune the catalysis by molecular design of the peptide precursor.
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| 2. |
- Bridges, Hannah R., et al.
(författare)
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Structure of inhibitor-bound mammalian complex I
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Ao resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I. The respiratory complex I (NADH:ubiquinone oxidoreductase) is a large redox-driven proton pump that initiates respiration in mitochondria. Here, the authors present the 3.0 angstrom cryo-EM structure of complex I from mouse heart mitochondria with the ubiquinone-analogue inhibitor piericidin A bound in the active site and with kinetic measurements and MD simulations they further show that this inhibitor acts competitively against the native ubiquinone-10 substrate.
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| 3. |
- Jussupow, Alexander, et al.
(författare)
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Effective Molecular Dynamics from Neural Network-Based Structure Prediction Models
- 2023
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 19:7, s. 1965-1975
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Tidskriftsartikel (refereegranskat)abstract
- Recent breakthroughs in neural network-based structure prediction methods, such as AlphaFold2 and RoseTTA-Fold, have dramatically improved the quality of computational protein structure prediction. These models also provide statistical confidence scores that can estimate uncertainties in the predicted structures, but it remains unclear to what extent these scores are related to the intrinsic conformational dynamics of proteins. Here, we compare AlphaFold2 prediction scores with explicit large-scale molecular dynamics simulations of 28 one-and two-domain proteins with varying degrees of flexibility. We demonstrate a strong correlation between the statistical prediction scores and the explicit motion derived from extensive atomistic molecular dynamics simulations and further derive an elastic network model based on the statistical scores of AlphFold2 (AF-ENM), which we benchmark in combination with coarse-grained molecular dynamics simulations. We show that our AF-ENM method reproduces the global protein dynamics with improved accuracy, providing a powerful way to derive effective molecular dynamics using neural network-based structure prediction models.
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| 4. |
- Jussupow, Alexander, et al.
(författare)
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Extended conformational states dominate the Hsp90 chaperone dynamics
- 2022
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 298:7
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Tidskriftsartikel (refereegranskat)abstract
- The heat shock protein 90 (Hsp90) is a molecular chaperone central to client protein folding and maturation in eukaryotic cells. During its chaperone cycle, Hsp90 undergoes ATPase-coupled large-scale conformational changes between open and closed states, where the N-terminal and middle domains of the protein form a compact dimerized conformation. However, the molecular principles of the switching motion between the open and closed states remain poorly understood. Here we show by integrating atomistic and coarse-grained molecular simulations with small-angle X-ray scattering experiments and NMR spectroscopy data that Hsp90 exhibits rich conformational dynamics modulated by the charged linker, which connects the N-terminal with the middle domain of the protein. We show that the dissociation of these domains is crucial for the conformational flexibility of the open state, with the separation distance controlled by a beta-sheet motif next to the linker region. Taken together, our results suggest that the conformational ensemble of Hsp90 comprises highly extended states, which could be functionally crucial for client processing.
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| 5. |
- Pöverlein, Maximilian C., et al.
(författare)
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Protein-Induced Membrane Strain Drives Supercomplex Formation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. Here we show that the formation of the mammalian I/III2 supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness, and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We also find that the SC assembly affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and entropic effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions.
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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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