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  • 1.
    Brodmerkel, Maxim
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Konijnenberg, Albert
    Sobott, Frank
    Marklund, Erik G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Molecular dynamics simulations reveal barrel opening during the unfolding of the outer membrane protein FhaCManuscript (preprint) (Other academic)
    Abstract [en]

    Many membrane proteins carry out gatekeeping and transport functions across the membrane, which makes them tremendously important for the control of what passes into or out from the cell. Their underlying dynamics can be very challenging to capture for structural biology techniques, for which structural heterogeneity often is problematic. Native ion mobility mass spectrometry (IM-MS) is capable of maintaining non-covalent interactions between biomolecules in vacuo, allowing for intact protein complexes from heterogeneous mixtures to be analysed with respect to their masses and structures, making it a powerful tool for structural biology. Recent collision induced unfolding (CIU) experiments, where IM-MS is used to track the unfolding of proteins after activation, were used to investigate the dynamics of the membrane protein FhaC from Bordetella pertussis. FhaC is a β-barrel transmembrane protein found in the outer membrane, where it secretes virulence factors to the outside of the bacterium, requiring notable changes to its structure. CIU cannot on its own provide detailed information about the structural changes along the unfolding pathway. Here, we use MD simulations to mimic the CIU experiments to see if the unfolding proceeds as expected, with cytoplasm-facing domains leading the unfolding, or if other parts of the structure breaks first. By separating our simulation data according to experimental CIU data from literature, we match the structures in the former to the unfolding states identified in the latter, and find that FhaC instead unfolds from a “seam” in the β-barrel. In a wider context, our investigation provides insights into the structural stability and unfolding dynamics of β-barrel membrane proteins and how they can be studied using a combination of CIU and MD.

  • 2.
    Brodmerkel, Maxim N.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607, Hamburg, Germany.
    Marklund, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Rehydration Post-orientation: Investigating Field-Induced Structural Changes via Computational Rehydration2023In: The Protein Journal, ISSN 1572-3887, E-ISSN 1875-8355, Vol. 42, no 3, p. 205-218Article in journal (Refereed)
    Abstract [en]

    Proteins can be oriented in the gas phase using strong electric fields, which brings advantages for structure determination using X-ray free electron lasers. Both the vacuum conditions and the electric-field exposure risk damaging the protein structures. Here, we employ molecular dynamics simulations to rehydrate and relax vacuum and electric-field exposed proteins in aqueous solution, which simulates a refinement of structure models derived from oriented gas-phase proteins. We find that the impact of the strong electric fields on the protein structures is of minor importance after rehydration, compared to that of vacuum exposure and ionization in electrospraying. The structures did not fully relax back to their native structure in solution on the simulated timescales of 200 ns, but they recover several features, including native-like intra-protein contacts, which suggests that the structures remain in a state from which the fully native structure is accessible. Our fndings imply that the electric fields used in native mass spectrometry are well below a destructive level, and suggest that structures inferred from X-ray difraction from gas-phase proteins are relevant for solution and in vivo conditions, at least after in silico rehydration.

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  • 3.
    Brodmerkel, Maxim N.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Uetrecht, Charlotte
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Deutsches Elektronen-Synchrotron, DESY, Notkestrasse 85, 22607 Hamburg, Germany.
    Marklund, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Collision induced unfolding and molecular dynamics simulations of norovirus capsid dimers reveal strain-specific stability profiles2024In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084Article in journal (Refereed)
    Abstract [en]

    Collision induced unfolding is method used with ion mobility mass spectrometry to examine protein structures and their stability. Such experiments yield information about higher order protein structures, yet are unable to provide details about the underlying processes. That information can however be provided using molecular dynamics simulations. Here, we investigate the collision induced unfolding of norovirus capsid dimers from the Norwalk and Kawasaki strains by employing molecular dynamics simulations over a range of temperatures, representing different levels of activation. The dimers have highly similar structures, but the activation reveals differences in the dynamics that arises in response to the activation.

  • 4.
    Brodmerkel, Maxim N.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Uetrecht, Charlotte
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Center for Free-Electron Laser Science, DESY, Notkestrasse 85, Hamburg, 22607, Germany.
    Marklund, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Stability and conformational memory of electrosprayed and rehydrated bacteriophage MS2 virus coat proteins2022In: Current Research in Structural Biology, E-ISSN 2665-928X, Vol. 4, p. 338-348Article in journal (Refereed)
    Abstract [en]

    Proteins are innately dynamic, which is important for their functions, but which also poses significant challenges when studying their structures. Gas-phase techniques can utilise separation and a range of sample manipulations to transcend some of the limitations of conventional techniques for structural biology in crystalline or solution phase, and isolate different states for separate interrogation. However, the transfer from solution to the gas phase risks affecting the structures, and it is unclear to what extent different conformations remain distinct in the gas phase, and if resolution in silico can recover the native conformations and their differences. Here, we use extensive molecular dynamics simulations to study the two distinct conformations of dimeric capsid protein of the MS2 bacteriophage. The protein undergoes notable restructuring of its peripheral parts in the gas phase, but subsequent simulation in solvent largely recovers the native structure. Our results suggest that despite some structural loss due to the experimental conditions, gas-phase structural biology techniques provide meaningful data that inform not only about the structures but also conformational dynamics of proteins.

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  • 5.
    Dawod, Ibrahim
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. European XFEL, Holzkoppel 4, DE-22869 Schenefeld, Germany.
    Cardoch, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    André, Tomas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    E, Juncheng
    European XFEL, Holzkoppel 4, DE-22869 Schenefeld, Germany.
    Mancuso, Adrian P.
    European XFEL, Holzkoppel 4, DE-22869 Schenefeld, Germany. Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85 DE-22607 Hamburg, Germany.
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    MolDStruct: modelling the dynamics and structure of matter exposed to ultrafast X-ray lasers with hybrid collisional-radiative/molecular dynamicsManuscript (preprint) (Other academic)
    Abstract [en]

    We describe a method to compute photon-matter interaction and atomic dynamics with X-ray lasers using a hybrid code based on classical molecular dynamics and collisional-radiative calculations. The forces between the atoms are dynamically computed based on changes to their electronic occupations and the free electron cloud created due to the irradiation of photons in the X-ray spectrum. The rapid transition from neutral solid matter to dense plasma phase allows the use of screened potentials, which reduces the number of non-bonded interactions required to compute. In combination with parallelization through domain decomposition, large-scale molecular dynamics and ionization induced by X-ray lasers can be followed. This method is applicable for large enough samples (solids, liquids, proteins, viruses, atomic clusters and crystals) that when exposed to an X-ray laser pulse turn into a plasma in the first few femtoseconds of the interaction. We show several examples of the applicability of the method and we quantify the sizes that the method is suitable for. For large systems, we investigate non-thermal heating and scattering of bulk water, which we compare to previous experiments. We simulate molecular dynamics of a protein crystal induced by an X-ray pump, X-ray probe scheme, and find good agreement of the damage dynamics with experiments. For single particle imaging, we simulate ultrafast dynamics of a methane cluster exposed to a femtosecond X-ray laser. In the context of coherent diffractive imaging we study the fragmentation as given by an X-ray pump X-ray probe setup to understand the evolution of radiation damage.

  • 6.
    De Santis, Emiliano
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Minicozzi, Velia
    Department of Physics, University of Rome Tor Vergata and Istituto di Fisica Nucleare (INFN), Via della Ricerca Scientifica 1 , 00133 Roma , Italy.
    Rossi, Giancarlo
    Hystorical Museum for Physics and Enrico Fermi Studies and Research Center, Department of Physics, University of Rome Tor Vergata and Istituto di Fisica Nucleare (INFN), Via della Ricerca Scientifica 1 , 00133 Roma , Italy;Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, Via Panisperna 89a , 00184 Roma , Italy.
    Stellato, Francesco
    Department of Physics, University of Rome Tor Vergata and Istituto di Fisica Nucleare (INFN), Via della Ricerca Scientifica 1 , 00133 Roma , Italy.
    Morante, Silvia
    Department of Physics, University of Rome Tor Vergata and Istituto di Fisica Nucleare (INFN), Via della Ricerca Scientifica 1 , 00133 Roma , Italy.
    Is styrene competitive for dopamine receptor binding?2022In: Biomolecular Concepts, ISSN 1868-503X, Vol. 13, no 1, p. 200-206Article in journal (Refereed)
    Abstract [en]

    The potential role of styrene oxide in altering the dopaminergic pathway in the ear is investigated by means of molecular docking and molecular dynamics simulations. We estimate the binding affinity of both styrene oxide and dopamine to the dopaminergic receptor DrD2 by computing the free-energy difference, ∆G, between the configuration where the ligand is bound to the receptor and the situation in which it is “infinitely” far away from it. The results show that the styrene oxide has a somewhat lower affinity for binding with respect to dopamine, which, however, may not be enough to prevent exogenous high concentration styrene oxide to compete with endogenous dopamine for DrD2 binding.

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  • 7.
    Galchenkova, Marina
    et al.
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany.
    Dawod, Ibrahim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. European XFEL, Holzkoppel 4, DE-22869 Schenefeld, Germany.
    Sprenger, Janina
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany.
    Oberthur, Dominik
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany.
    Cardoch, Sebastian
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Grånäs, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Chapman, Henry N.
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany. Centre for Ultrafast Imaging, Universität Hamburg, 22761 Hamburg, Germany. Department of Physics, Universität Hamburg, 22761 Hamburg, Germany .
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany.
    Yefanov, Oleksandr
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestraße 85, DE-22607 Hamburg, Germany.
    Radiation damage in a hemoglobin crystal studied with an X-ray free-electron laserManuscript (preprint) (Other academic)
    Abstract [en]

    Radiation damage is a topic since the dawn of X-ray crystallography, and has gained new importance in the era of X-ray free-electron lasers (XFELs), due to their unprecedented brilliance and pulse duration. One of the driving questions has been how short the XFEL pulse has to be for the structural information to be ”damage free”. Here we compare data from Serial Femtosecond Crystallography (SFX) experiments conducted with a 3 fs and a 10 fs X-ray pulse. We conclude that even if the estimated displacement of atoms in the sample is an order of magnitude larger in the case of the 10 fs experiment, the displacement is still too small to affect the experimental data at a resolution relevant for structural determination.

  • 8. Kierspel, Thomas
    et al.
    Kadek, Alan
    Barran, Perdita
    Bellina, Bruno
    Bijedic N, Adi
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Brodmerkel, Maxim N.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Commandeur, Jan
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Centre for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, E22607, Hamburg, Germany.
    Damjanović, Tomislav
    Dawod, Ibrahim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. European XFEL, Holzkoppel 4, 22869, Schenefeld, Germany.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Lekkas, Alexandros
    Lorenzen, Kristina
    López Morillo, Luis
    Mandl, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. University of Applied Sciences Technikum Wien, Höchstädtpl. 6, 1200, Vienna, Austria.
    Marklund, Erik G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Papanastasiou, Dimitris
    Ramakers, Lennart A. I.
    Schweikhard, Lutz
    Simke, Florian
    Sinelnikova, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Smyrnakis, Athanasios
    Timneanu, Nicusor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Uetrecht, Charlotte
    Coherent diffractive imaging of proteins and viral capsids: simulating MS SPIDOC2023In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 415, no 18 SI, p. 4209-4220Article in journal (Refereed)
    Abstract [en]

    MS SPIDOC is a novel sample delivery system designed for single (isolated) particle imaging at X-ray Free-Electron Lasers that is adaptable towards most large-scale facility beamlines. Biological samples can range from small proteins to MDa particles. Following nano-electrospray ionization, ionic samples can be m/z-filtered and structurally separated before being oriented at the interaction zone. Here, we present the simulation package developed alongside this prototype. The first part describes how the front-to-end ion trajectory simulations have been conducted. Highlighted is a quadrant lens; a simple but efficient device that steers the ion beam within the vicinity of the strong DC orientation field in the interaction zone to ensure spatial overlap with the X-rays. The second part focuses on protein orientation and discusses its potential with respect to diffractive imaging methods. Last, coherent diffractive imaging of prototypical T = 1 and T = 3 norovirus capsids is shown. We use realistic experimental parameters from the SPB/SFX instrument at the European XFEL to demonstrate that low-resolution diffractive imaging data (q < 0.3 nm−1) can be collected with only a few X-ray pulses. Such low-resolution data are sufficient to distinguish between both symmetries of the capsids, allowing to probe low abundant species in a beam if MS SPIDOC is used as sample delivery.

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  • 9.
    Lindblad, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Inorganic Chemistry. Lund Univ, Dept Phys, Box 118, S-22100 Lund, Sweden.;Helmholtz Zentrum Berlin Mat & Energie, Abt Hochempfindl Rontgenspektroskopie, Albert Einstein Str 15, D-12489 Berlin, Germany..
    Kjellsson, Ludvig
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. European XFEL GmbH, Holzkoppel 4, 22869 Schenefeld, Germany..
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Zamudio-Bayer, Vicente
    von Issendorff, Bernd
    Sorensen, Stacey L.
    Lau, J. Tobias
    Hua, Weijie
    Carravetta, Vincenzo
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Ågren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Couto, Rafael Carvalho
    Experimental and theoretical near-edge x-ray-absorption fine-structure studies of NO+2022In: Physical Review A: covering atomic, molecular, and optical physics and quantum information, ISSN 2469-9926, E-ISSN 2469-9934, Vol. 106, no 4, article id 042814Article in journal (Refereed)
    Abstract [en]

    Experimental near-edge x-ray-absorption fine-structure (NEXAFS) spectra of the nitrosonium NO+ ion are presented and theoretically analyzed. While neutral NO has an open shell, the cation is a closed-shell species, which for NEXAFS leads to the simplicity of a closed-shell spectrum. Compared to neutral NO, the electrons in the cation experience a stronger Coulomb potential, which introduces a shift of the ionization potential towards higher energies, a depletion of intensity in a large interval above the pi* resonance, and a shift of the sigma* resonance from the continuum to below the ionization threshold. NEXAFS features at the nitrogen and oxygen K edges of NO+ are compared, as well as NEXAFS features at the nitrogen edges of the isoelectronic closed-shell species NO+, N2, and N2H+.

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  • 10.
    Nucara, Alessandro
    et al.
    Sapienza Univ Rome, Dept Phys, Ple A Moro 5, I-00185 Rome, Italy..
    Ripanti, Francesca
    Univ Perugia, Dept Phys & Geol, Via Alessandro Pascoli, I-06123 Perugia, Italy..
    Sennato, Simona
    Sapienza Univ, Dept Phys, CNR ISC Sede Sapienza, Ple A Moro 5, I-00185 Rome, Italy..
    Nisini, Giacomo
    Sapienza Univ Rome, Dept Phys, Ple A Moro 5, I-00185 Rome, Italy..
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Sefat, Mahta
    Tor Vergata Univ Rome, Sch Pharm, Via Ric Sci 1, I-00133 Rome, Italy..
    Carbonaro, Marina
    Council Agr Res & Econ CREA, Res Ctr Food & Nutr, Via Ardeatina 546, I-00178 Rome, Italy..
    Mango, Dalila
    Tor Vergata Univ Rome, Sch Pharm, Via Ric Sci 1, I-00133 Rome, Italy.;European Brain Res Inst, Lab Pharmacol Synapt Plast, I-00161 Rome, Italy..
    Minicozzi, Velia
    Tor Vergata Univ Rome, Dept Phys, Via Ric Sci 1, I-00133 Rome, Italy.;Tor Vergata Univ Rome, Ist Nazl Fis Nucl, Via Ric Sci 1, I-00133 Rome, Italy..
    Carbone, Marilena
    Univ Roma Tor Vergata, Dept Chem Sci & Technol, Via Ric Sci 1, I-00133 Rome, Italy..
    Influence of Cortisol on the Fibril Formation Kinetics of A beta 42 Peptide: A Multi-Technical Approach2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 11, article id 6007Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta peptide (A beta) aggregates are known to be correlated with pathological neurodegenerative diseases. The fibril formation process of such peptides in solution is influenced by several factors, such as the ionic strength of the buffer, concentration, pH, and presence of other molecules, just to mention a few. In this paper, we report a detailed analysis of in vitro A beta 42 fibril formation in the presence of cortisol at different relative concentrations. The thioflavin T fluorescence assay allowed us to monitor the fibril formation kinetics, while a morphological characterization of the aggregates was obtained by atomic force microscopy. Moreover, infrared absorption spectroscopy was exploited to investigate the secondary structure changes along the fibril formation path. Molecular dynamics calculations allowed us to understand the intermolecular interactions with cortisol. The combined results demonstrated the influence of cortisol on the fibril formation process: indeed, at cortisol-A beta 42 concentration ratio (rho) close to 0.1 a faster organization of A beta 42 fragments into fibrils is promoted, while for rho = 1 the formation of fibrils is completely inhibited.

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  • 11.
    Pihlava, Lassi
    et al.
    Univ Turku, Dept Phys & Astron, FI-20014 Turku, Finland..
    Svensson, Pamela
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Kukk, Edwin
    Univ Turku, Dept Phys & Astron, FI-20014 Turku, Finland..
    Kooser, Kuno
    Univ Tartu, Inst Phys, W Ostwald 1, EST-50411 Tartu, Estonia..
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Tonisoo, Arvo
    Univ Tartu, Inst Phys, W Ostwald 1, EST-50411 Tartu, Estonia..
    Käämbre, Tanel
    Univ Tartu, Inst Phys, W Ostwald 1, EST-50411 Tartu, Estonia..
    André, Tomas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Akiyama, Tomoko
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Hessenthaler, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Giehr, Flavia
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Björneholm, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Ctr Free Electron Laser Sci, DESY, D-22607 Hamburg, Germany..
    Berholts, Marta
    Univ Tartu, Inst Phys, W Ostwald 1, EST-50411 Tartu, Estonia..
    Shell-dependent photofragmentation dynamics of a heavy-atom-containing bifunctional nitroimidazole radiosensitizer2024In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 26, no 11, p. 8879-8890Article in journal (Refereed)
    Abstract [en]

    Radiation therapy uses ionizing radiation to break chemical bonds in cancer cells, thereby causing DNA damage and leading to cell death. The therapeutic effectiveness can be further increased by making the tumor cells more sensitive to radiation. Here, we investigate the role of the initial halogen atom core hole on the photofragmentation dynamics of 2-bromo-5-iodo-4-nitroimidazole, a potential bifunctional radiosensitizer. Bromine and iodine atoms were included in the molecule to increase the photoionization cross-section of the radiosensitizer at higher photon energies. The fragmentation dynamics of the molecule was studied experimentally in the gas phase using photoelectron-photoion-photoion coincidence spectroscopy and computationally using Born-Oppenheimer molecular dynamics. We observed significant changes between shallow core (I 4d, Br 3d) and deep core (I 3d) ionization in fragment formation and their kinetic energies. Despite the fact, that the ions ejected after deep core ionization have higher kinetic energies, we show that in a cellular environment, the ion spread is not much larger, keeping the damage well-localized. A study on photodissociation dynamics of 2-bromo-5-iodo-nitroimidazole - a model radiosensitizer - using coincidence spectroscopy and computational methods.

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  • 12.
    Sinelnikova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Mandl, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. ty of Applied Sciences Technikum Wien, Wien, Austria.
    Agelii, Harald
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Grånäs, Oscar
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Marklund, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Center for Free-Electron Laser Science, DESY,Hamburg, Germany.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Protein orientation in time-dependent electric fields: orientation before destruction2021In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 120, no 17, p. 3709-3717, article id S0006-3495(21)00603-2Article in journal (Refereed)
    Abstract [en]

    Proteins often have nonzero electric dipole moments, making them interact with external electric fields and offering a means for controlling their orientation. One application that is known to benefit from orientation control is single-particle imaging with x-ray free-electron lasers, in which diffraction is recorded from proteins in the gas phase to determine their structures. To this point, theoretical investigations into this phenomenon have assumed that the field experienced by the proteins is constant or a perfect step function, whereas any real-world pulse will be smooth. Here, we explore the possibility of orienting gas-phase proteins using time-dependent electric fields. We performed ab initio simulations to estimate the field strength required to break protein bonds, with 45 V/nm as a breaking point value. We then simulated ubiquitin in time-dependent electric fields using classical molecular dynamics. The minimal field strength required for orientation within 10 ns was on the order of 0.5 V/nm. Although high fields can be destructive for the structure, the structures in our simulations were preserved until orientation was achieved regardless of field strength, a principle we denote "orientation before destruction."

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  • 13.
    Wollter, August
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    De Santis, Emiliano
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Ekeberg, Tomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Marklund, Erik G.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Chemical and Bio-Molecular Physics. Deutsch Elekt Synchrotron DESY, Ctr Free Elect Laser Sci CFEL, Notkestr 85, D-22607 Hamburg, Germany..
    Enhanced EMC-Advantages of partially known orientations in x-ray single particle imaging2024In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 160, no 11, article id 114108Article in journal (Refereed)
    Abstract [en]

    Single particle imaging of proteins in the gas phase with x-ray free-electron lasers holds great potential to study fast protein dynamics, but is currently limited by weak and noisy data. A further challenge is to discover the proteins' orientation as each protein is randomly oriented when exposed to x-rays. Algorithms such as the expand, maximize, and compress (EMC) exist that can solve the orientation problem and reconstruct the three-dimensional diffraction intensity space, given sufficient measurements. If information about orientation were known, for example, by using an electric field to orient the particles, the reconstruction would benefit and potentially reach better results. We used simulated diffraction experiments to test how the reconstructions from EMC improve with particles' orientation to a preferred axis. Our reconstructions converged to correct maps of the three-dimensional diffraction space with fewer measurements if biased orientation information was considered. Even for a moderate bias, there was still significant improvement. Biased orientations also substantially improved the results in the case of missing central information, in particular in the case of small datasets. The effects were even more significant when adding a background with 50% the strength of the averaged diffraction signal photons to the diffraction patterns, sometimes reducing the data requirement for convergence by a factor of 10. This demonstrates the usefulness of having biased orientation information in single particle imaging experiments, even for a weaker bias than what was previously known. This could be a key component in overcoming the problems with background noise that currently plague these experiments.

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