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1699 Publications visible to you, out of a total of 1699
The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

Abstract (Expand)

Although it is well established that the SARS-CoV-2 spike glycoprotein binds to the host cell ACE2 receptor to initiate infection, far less is known about the tissue tropism and host cell susceptibility …susceptibility to the virus. Differential expression across different cell types of heparan sulfate (HS) proteoglycans, with variably sulfated glycosaminoglycans (GAGs), and their synergistic interactions with host and viral N-glycans may contribute to tissue tropism and host cell susceptibility. Nevertheless, their contribution remains unclear since HS and N-glycans evade experimental characterization. We, therefore, carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration molecular dynamics simulations, of the fully glycosylated spike:ACE2 complex with and without highly sulfated GAG chains bound. By considering the model GAGs as surrogates for the highly sulfated HS expressed in lung cells, we identified key cell entry mechanisms of spike SARS-CoV-2. We find that HS promotes structural and energetic stabilization of the active conformation of the spike receptor-binding domain (RBD) and reorientation of ACE2 toward the N-terminal domain in the same spike subunit as the RBD. Spike and ACE2 N-glycans exert synergistic effects, promoting better packing, strengthening the protein:protein interaction, and prolonging the residence time of the complex. ACE2 and HS binding trigger rearrangement of the S2’ functional protease cleavage site through allosteric interdomain communication. These results thus show that HS has a multifaceted role in facilitating SARS-CoV-2 infection, and they provide a mechanistic basis for the development of GAG derivatives with anti-SARS-CoV-2 potential.

Authors: Giulia Paiardi, Matheus Ferraz, Marco Rusnati, Rebecca C. Wade

Date Published: 22nd Oct 2024

Publication Type: Journal

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome 2B4

Abstract (Expand)

Cytochrome P450 2B4 (CYP 2B4) is one of the best characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The …n drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full-length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse-grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation-dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re-entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.

Authors: Sungho Bosco Han, Jonathan Teuffel, Goutam Mukherjee, Rebecca C. Wade

Date Published: 1st Oct 2024

Publication Type: Journal

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4

Abstract (Expand)

Abstract Cytochrome P450 2B4 (CYP 2B4) is one of the best‐characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known …hich metabolize most known drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full‐length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse‐grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation‐dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re‐entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates the binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.

Authors: Sungho Bosco Han, Jonathan Teuffel, Goutam Mukherjee, Rebecca C. Wade

Date Published: 1st Oct 2024

Publication Type: Journal

Merger seismology: Distinguishing massive merger products from genuine single stars using asteroseismology

Abstract (Expand)

Products of stellar mergers are predicted to be common in stellar populations and can potentially explain stars with peculiar properties. When the merger occurs after the initially more massive star …ar has evolved into the Hertzsprung gap, the merger product may remain in the blue part of the Hertzsprung–Russell diagram for millions of years. Such objects could, therefore, explain the overabundance of observed blue stars, such as blue supergiants. However, it is currently not straightforward to distinguish merger products from genuine single stars or other stars with similar surface diagnostics. In this work, we made detailed asteroseismic comparisons between models of massive post-main-sequence merger products and genuine single stars to identify which asteroseismic diagnostics can be used to distinguish them. In doing so, we developed tools for the relatively young field of merger seismology. Genuine single stars in the Hertzsprung gap are fully radiative, while merger products have a convective He-burning core and convective H-burning shell while occupying similar locations in the Hertzsprung–Russell diagram. These major structural differences are reflected in lower asymptotic period spacing values for merger products and the appearance of deep dips in their period spacing patterns. Our genuine single-star models with masses above roughly 11.4 solar masses develop short-lived intermediate convective zones during their Hertzsprung gap evolution. This also leads to deep dips in their period spacing patterns. Because of the lack of a convective core, merger products and genuine single stars can be distinguished based on their asymptotic period spacing value in this mass range. We performed the comparisons with and without the effects of slow rotation included in the pulsation equations and conclude that the two types of stars are seismically distinguishable in both cases. The observability of the distinguishing asteroseismic features of merger products can now be assessed and exploited in practice.

Authors: J. Henneco, F. R. N. Schneider, S. Hekker, C. Aerts

Date Published: 1st Oct 2024

Publication Type: Journal

Merger seismology: Distinguishing massive merger products from genuine single stars using asteroseismology

Abstract (Expand)

Products of stellar mergers are predicted to be common in stellar populations and can potentially explain stars with peculiar properties. When the merger occurs after the initially more massive star … has evolved into the Hertzsprung gap, the merger product may remain in the blue part of the Hertzsprung–Russell diagram for millions of years. Such objects could, therefore, explain the overabundance of observed blue stars, such as blue supergiants. However, it is currently not straightforward to distinguish merger products from genuine single stars or other stars with similar surface diagnostics. In this work, we made detailed asteroseismic comparisons between models of massive post-main-sequence merger products and genuine single stars to identify which asteroseismic diagnostics can be used to distinguish them. In doing so, we developed tools for the relatively young field of merger seismology. Genuine single stars in the Hertzsprung gap are fully radiative, while merger products have a convective He-burning core and convective H-burning shell while occupying similar locations in the Hertzsprung–Russell diagram. These major structural differences are reflected in lower asymptotic period spacing values for merger products and the appearance of deep dips in their period spacing patterns. Our genuine single-star models with masses above roughly 11.4 solar masses develop short-lived intermediate convective zones during their Hertzsprung gap evolution. This also leads to deep dips in their period spacing patterns. Because of the lack of a convective core, merger products and genuine single stars can be distinguished based on their asymptotic period spacing value in this mass range. We performed the comparisons with and without the effects of slow rotation included in the pulsation equations and conclude that the two types of stars are seismically distinguishable in both cases. The observability of the distinguishing asteroseismic features of merger products can now be assessed and exploited in practice.

Authors: J. Henneco, F. R. N. Schneider, S. Hekker, C. Aerts

Date Published: 1st Oct 2024

Publication Type: Journal

The radial modes of stars with suppressed dipole modes

Abstract (Expand)

Context. The Kepler space mission provided high-quality light curves for more than 16 000 red giants. The global stellar oscillations extracted from these light curves carry information about the … interior of the stars. Several hundred red giants were found to have low amplitudes in their dipole modes (i.e. they are suppressed dipole-mode stars). A number of hypotheses (involving e.g. a magnetic field, binarity, or resonant mode coupling) have been proposed to explain the suppression of the modes, yet none has been confirmed. Aims. We aim to gain insight into the mechanism at play in suppressed dipole-mode stars by investigating the mode properties (linewidths, heights, and amplitudes) of the radial oscillation modes of red giants with suppressed dipole modes. Methods.We selected from the literature suppressed dipole-mode stars and compared the radial-mode properties of these stars to the radial-mode properties of stars in two control samples of stars with typical (i.e. non-suppressed) dipole modes. Results. We find that the radial-mode properties of the suppressed dipole-mode stars are consistent with the ones in our control samples, and hence not affected by the suppression mechanism. Conclusions. From this we conclude that (1) the balance between the excitation and damping in radial modes is unaffected by the suppression, and by extrapolation the excitation of the non-radial modes is not affected either; and (2) the damping of the radial modes induced by the suppression mechanism is significantly less than the damping from turbulent convective motion, suggesting that the additional damping originates from the more central non-convective regions of the star, to which the radial modes are least sensitive.

Authors: Q. Coppée, J. Müller, M. Bazot, S. Hekker

Date Published: 1st Oct 2024

Publication Type: Journal

Validation and Cross‑Species Comparison of scRNA‑seq Trajectory Inference Algorithms

Abstract

Not specified

Authors: Eric Laudemann, Alexandros Stamatakis

Date Published: 1st Oct 2024

Publication Type: Master's Thesis

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