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  • Manzetti, Sergio, 1975- (författare)
  • Computational Ecotoxicology
  • 2022
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Human society has progressed by polluting ecosystems since at least the early industrial revolution. Large amounts of harmful chemical compounds have been dispersed in soils, seas, ground waters and wildlife habitats by industrial and anthropomorphic activities over the last two centuries, leading to a persistent toxicological load on the environment. Pollution is a threat to biodiversity, to the health of ecosystems, and to all living organisms. Advances in environmental sciences are needed so that pollutants can be distinguished from harmless compounds. New methods could ease the enormous task of sorting out hazardous chemicals, and also facilitate the study of existing problems in ecotoxicology, which are often hampered by insufficient data. In our research, we apply the methods of computational chemistry to predict the interactions of various toxins, carcinogens, nanoparticles and xenobiotics with proteins, DNA, and cell membranes. Methods such as molecular dynamics simulations, docking, and quantum chemistry are at the core of these studies, each having its role in facilitating the enormous task of transforming in vitro ecotoxicology to in silico ecotoxicology. We perform detailed studies of a few compounds and receptors, as well as larger, more comprehensive groups of compounds. We also outline approaches for drawing computational conclusions about the molecular behaviour of various potential environmental toxins by modelling their interactions with DNA and proteins, and we use partition coefficients to describe their ability to permeate the cell membrane. Methods for studying the purification of pollutants from essential sources, such as water, are proposed. We also investigate the emerging problem of nanoparticle pollution and propose computational approaches to model the formation of nanoparticles from combustion emissions and the interactions of such particles with atmospheric components.
  • Stah, Olga, 1983- (författare)
  • Prokaryotic respiratory supercomplexes : Studies of interactions between complexes III and IV
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Respiratory processes for cellular energy conversion are carried out by the membrane-associated enzymes of the electron transfer chain (ETC). In recent years there has been emerging data showing that the members of the ETC organize into higher-level assemblies called supercomplexes (SCs) whose functional relevance is not yet fully understood. SCs composed of complexes III (cytochrome (cyt.) bc1 complex) and IV (cyt. c oxidase) are the most common. The small electron-carrier protein cyt. c shuttles electrons between complexes III and IV. In mitochondria-like ETCs cyt. c is present only in a soluble form, while in some bacteria it has additional membrane-anchored analogs or is fused to complex III forming the cyt. cc subunit, as in actinobacteria.We determined the structure of the obligate III/IV SC from actinobacterium Mycobacterium (M.) smegmatis with cryo-electron microscopy. The structure showed that the distances between the co-factors of the SC are short enough for electron transfer with the catalytically relevant rates. Complexes III and IV within the SC were intertwined. In particular, the entrance to the D-proton pathway of complex IV was shielded by a loop of the QcrB subunit of complex III, possibly influencing proton uptake characteristics. Furthermore, superoxide dismutase was shown to be an integral part of the M. smegmatis SC, which might have a functional role in the energy conservation by the SC.With the goal to unravel the structure-function relationships between complexes III and IV in the actinobacterial SCs, we investigated the charge transfer kinetics in SCs on a single-turnover time scale. Using time-resolved spectroscopic techniques we have determined the rates of electron and proton transfer upon oxidation of reduced SCs of M. smegmatis and another actinobacterium Corynebacterium glutamicum. Electron transfer from cyt. cc in complex III to the primary redox center CuA in complex IV was not rate-limiting for the SC turnover. In contrast to the canonical complex IV, certain reaction steps in SC were not pH-dependent and proton uptake kinetics through the D-pathway of complex IV was altered showing much slower kinetics. This suggests that the QcrB loop of complex III, which blocks the entrance to the D-pathway, modulates the kinetics of proton uptake in complex IV. In another study, we showed the existence of a non-obligate supercomplex in the alfa-proteobacterium Rhodobacter (R.) sphaeroides. This SC was purified and characterized biochemically. We concluded that complexes III and IV interact via the membrane-anchored version of cyt. c (MA-cyt. c), which is expressed in the bacterium in addition to the soluble variant. MA-cyt. c most likely plays a central role in forming the SC in R. sphaeroides by functionally connecting complexes III and IV.In addition to being an electron shuttle, in eukaryotes cyt. c participates in apoptosis. We investigated the consequences of anchoring the cyt. c to the membrane, similar to MA-cyt. c in R. sphaeroides, in a single-cell eukaryote Saccharomyces cerevisiae, thereby not allowing the release of cyt. c from the intermembrane space of mitochondria during the induced apoptosis.The work presented in this thesis increases our understanding of the general function-structure relationships of respiratory SCs and might have applications in potential drug development.
  • Bondarenko, Vasyl, et al. (författare)
  • Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization
  • 2023
  • Ingår i: ACS Chemical Neuroscience. - : American Chemical Society. - 1948-7193. ; 14:6, s. 1156-1165
  • Tidskriftsartikel (refereegranskat)abstract
    • The α7 nicotinic acetylcholine receptor (α7nAChR) mediates signaling in the central nervous system and cholinergic anti-inflammatory pathways. Ivermectin is a positive allosteric modulator of a full-length α7nAChR and an agonist of the α7nAChR construct containing transmembrane (TMD) and intracellular (ICD) domains, but structural insights of the binding have not previously been determined. Here, combining nuclear magnetic resonance as a primary experimental tool with Rosetta comparative modeling and molecular dynamics simulations, we have revealed details of ivermectin binding to the α7nAChR TMD + ICD and corresponding structural changes in an ivermectin-induced desensitized state. Ivermectin binding was stabilized predominantly by hydrophobic interactions from interfacial residues between adjacent subunits near the extracellular end of the TMD, where the inter-subunit gap was substantially expanded in comparison to the apo structure. The ion-permeation pathway showed a profile distinctly different from the resting-state profile but similar to profiles of desensitized α7nAChR. The ICD also exhibited structural changes, including reorientation of the MX and h3 helices relative to the channel axis. The resulting structures of the α7nAChR TMD + ICD in complex with ivermectin provide opportunities for discovering new modulators of therapeutic potential and exploring the structural basis of cytoplasmic signaling under different α7nAChR functional states.
  • Choudhury, Koushik, et al. (författare)
  • An alpha-pi transition in S6 shapes the conformational cycle of the bacterial sodium channel NavAb
  • 2022
  • Ingår i: The Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 155:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Voltage-gated sodium channels play an important role in electrical signaling in excitable cells. In response to changes in membrane potential, they cycle between nonconducting and conducting conformations. With recent advances in structural biology, structures of sodium channels have been captured in several distinct conformations, which are thought to represent different functional states. However, it has been difficult to capture the intrinsically transient open state. We recently showed that a proposed open state of the bacterial sodium channel NavMs was not conductive and that a conformational change involving a transition to a pi-helix in the pore-lining S6 helix converted this structure into a conducting state. However, the relevance of this structural feature in other sodium channels, and its implications for the broader gating cycle, remained unclear. Here, we propose a comparable open state of another class of bacterial channel from Aliarcobacter butzleri (NavAb) with characteristic pore hydration, ion permeation, and drug binding properties. Furthermore, we show that a pi-helix transition can lead to pore opening and that such a conformational change blocks fenestrations in the inner helix bundle. We also discover that a region in the C-terminal domain can undergo a disordering transition proposed to be important for pore opening. These results support a role for a pi-helix transition in the opening of NavAb, enabling new proposals for the structural annotation and drug modulation mechanisms in this important sodium channel model. We propose a new conformational cycle for NavAb wherein an alpha- to pi-helix transition in S6 and disordering of the neck region of the C-terminal domain is important for pore opening.
  • Giron, Carolina Corrêa, et al. (författare)
  • Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies
  • 2023
  • Ingår i: Journal of Biomolecular Structure and Dynamics. - : Taylor & Francis. - 0739-1102 .- 1538-0254. ; 41:12, s. 5707-5727
  • Forskningsöversikt (refereegranskat)abstract
    • SARS-CoV-2 remains a health threat with the continuous emergence of new variants. This work aims to expand the knowledge about the SARS-CoV-2 receptor-binding domain (RBD) interactions with cell receptors and monoclonal antibodies (mAbs). By using constant-pH Monte Carlo simulations, the free energy of interactions between the RBD from different variants and several partners (Angiotensin-Converting Enzyme-2 (ACE2) polymorphisms and various mAbs) were predicted. Computed RBD-ACE2-binding affinities were higher for two ACE2 polymorphisms (rs142984500 and rs4646116) typically found in Europeans which indicates a genetic susceptibility. This is amplified for Omicron (BA.1) and its sublineages BA.2 and BA.3. The antibody landscape was computationally investigated with the largest set of mAbs so far in the literature. From the 32 studied binders, groups of mAbs were identified from weak to strong binding affinities (e.g. S2K146). These mAbs with strong binding capacity and especially their combination are amenable to experimentation and clinical trials because of their high predicted binding affinities and possible neutralization potential for current known virus mutations and a universal coronavirus.
  • Lycksell, Marie, et al. (författare)
  • Probing solution structure of the pentameric ligand-gated ion channel GLIC by small-angle neutron scattering
  • 2021
  • 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. ; 118:37
  • Tidskriftsartikel (refereegranskat)abstract
    • Pentameric ligand-gated ion channels undergo subtle conformational cycling to control electrochemical signal transduction in many kingdoms of life. Several crystal structures have now been reported in this family, but the functional relevance of such models remains unclear. Here, we used small-angle neutron scattering (SANS) to probe ambient solution-phase properties of the pHgated bacterial ion channel GLIC under resting and activating conditions. Data collection was optimized by inline paused-flow size-exclusion chromatography, and exchanging into deuterated detergent to hide the micelle contribution. Resting-state GLIC was the best-fit crystal structure to SANS curves, with no evidence for divergent mechanisms. Moreover, enhanced-sampling moleculardynamics simulations enabled differential modeling in resting versus activating conditions, with the latter corresponding to an intermediate ensemble of both the extracellular and transmembrane domains. This work demonstrates state-dependent changes in a pentameric ion channel by SANS, an increasingly accessible method for macromolecular characterization with the coming generation of neutron sources.
  • Ulmefors, Hanna, et al. (författare)
  • Formation of Supported Lipid Bilayers Derived from Vesicles of Various Compositional Complexity on Conducting Polymer/Silica Substrates
  • 2021
  • Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 37:18, s. 5494-5505
  • Tidskriftsartikel (refereegranskat)abstract
    • Supported lipid bilayers (SLBs) serve important roles as minimalistic models of cellular membranes in multiple diagnostic and pharmaceutical applications as well as in the strive to gain fundamental insights about their complex biological function. To further expand the utility of SLBs, there is a need to go beyond simple lipid compositions to thereby better mimic the complexity of native cell membranes, while simultaneously retaining their compatibility with a versatile range of analytical platforms. To meet this demand, we have in this work explored SLB formation on PEDOT:PSS/silica nanoparticle composite films and mesoporous silica films, both capable of transporting ions to an underlying conducting PEDOT:PSS film. The SLB formation process was evaluated by using the quartz crystal microbalance with dissipation (QCM-D) monitoring, total internal reflection fluorescence (TIRF) microscopy, and fluorescence recovery after photobleaching (FRAP) for membranes made of pure synthetic lipids with or without the reconstituted membrane protein β-secretase 1 (BACE1) as well as cell-derived native lipid vesicles containing overexpressed BACE1. The mesoporous silica thin film was superior to the PEDOT:PSS/silica nanoparticle composite, providing successful formation of bilayers with high lateral mobility and low defect density even for the most complex native cell membranes.
  • Zhuang, Yuxuan, et al. (författare)
  • Differential interactions of resting, activated, and desensitized states of the α7 nicotinic acetylcholine receptor with lipidic modulators
  • 2022
  • 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. ; 119:43
  • Tidskriftsartikel (refereegranskat)abstract
    • The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that modulates neuronal excitability, largely by allowing Ca2+ permeation. Agonist binding promotes transition from a resting state to an activated state, and then rapidly to a desensitized state. Recently, cryogenic electron microscopy (cryo-EM) structures of the human α7 receptor in nanodiscs were reported in multiple conformations. These were selectively stabilized by inhibitory, activating, or potentiating compounds. However, the functional annotation of these structures and their differential interactions with unresolved lipids and ligands remain incomplete. Here, we characterized their ion permeation, membrane interactions, and ligand binding using computational electrophysiology, free-energy calculations, and coarse-grained molecular dynamics. In contrast to nonconductive structures in apparent resting and desensitized states, the structure determined in the presence of the potentiator PNU-120596 was consistent with an activated state permeable to Ca2+. Transition to this state was associated with compression and rearrangement of the membrane, particularly in the vicinity of the peripheral MX helix. An intersubunit transmembrane site was implicated in selective binding of either PNU-120596 in the activated state or cholesterol in the desensitized state. This substantiates functional assignment of all three lipid-embedded α7-receptor structures with ion-permeation simulations. It also proposes testable models of their state-dependent interactions with lipophilic ligands, including a mechanism for allosteric modulation at the transmembrane subunit interface. 
  • Colombo, Gloria, et al. (författare)
  • A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes
  • 2022
  • Ingår i: Nature Neuroscience. - : Springer Nature. - 1097-6256 .- 1546-1726. ; 25:10, s. 1379-
  • Tidskriftsartikel (refereegranskat)abstract
    • Environmental cues influence the highly dynamic morphology of microglia. Strategies to characterize these changes usually involve user-selected morphometric features, which preclude the identification of a spectrum of context-dependent morphological phenotypes. Here we develop MorphOMICs, a topological data analysis approach, which enables semiautomatic mapping of microglial morphology into an atlas of cue-dependent phenotypes and overcomes feature-selection biases and biological variability. We extract spatially heterogeneous and sexually dimorphic morphological phenotypes for seven adult mouse brain regions. This sex-specific phenotype declines with maturation but increases over the disease trajectories in two neurodegeneration mouse models, with females showing a faster morphological shift in affected brain regions. Remarkably, microglia morphologies reflect an adaptation upon repeated exposure to ketamine anesthesia and do not recover to control morphologies. Finally, we demonstrate that both long primary processes and short terminal processes provide distinct insights to morphological phenotypes. MorphOMICs opens a new perspective to characterize microglial morphology.
  • Dahlberg, Tobias, 1990-, et al. (författare)
  • Unveiling molecular interactions that stabilize bacterial adhesion pili
  • 2022
  • Ingår i: Biophysical Journal. - : Biophysical Society. - 0006-3495 .- 1542-0086. ; 121:11, s. 2096-2106
  • Tidskriftsartikel (refereegranskat)abstract
    • Adhesion pili assembled by the chaperone-usher pathway are superelastic helical filaments on the surface of bacteria, optimized for attachment to target cells. Here, we investigate the biophysical function and structural interactions that stabilize P pili from uropathogenic bacteria. Using optical tweezers, we measure P pilus subunit-subunit interaction dynamics and show that pilus compliance is contour-length dependent. Atomic details of subunit-subunit interactions of pili under tension are shown using steered molecular dynamics (sMD) simulations. sMD results also indicate that the N-terminal “staple” region of P pili, which provides interactions with pilins that are four and five subunits away, significantly stabilizes the helical filament structure. These data are consistent with previous structural data, and suggest that more layer-to-layer interactions could compensate for the lack of a staple in type 1 pili. This study informs our understanding of essential structural and dynamic features of adhesion pili, supporting the hypothesis that the function of pili is critically dependent on their structure and biophysical properties.
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