- by Arcario, M. J., Wu-Chen, E. J., Henin, J., Brannigan, G., Cheng, W. W.-L.Open-channel structures have been determined of multiple pentameric ligand-gated ion channels (pLGIC), including the prokaryotic model pLGIC, ELIC (Erwinia ligand-gated ion channel). For many of these structures, it remains uncertain whether they represent the physiologic open-channel state because the conditions used for structure determination do not match those of functional measurements in cell membranes. Here, molecular dynamics (MD) simulation is used to examine the ion conduction properties of the ELIC open-channel structure, which was determined using a non-desensitizing mutant called […]
- by Woody Santos, J. B., Chen, L., Miranda Quintana, R. A.We present mdBIRCH, an online clustering method that adapts the BIRCH CF-tree to molecular dynamics (MD) data by using a merge test calibrated directly to RMSD. Each arriving frame is routed to the nearest centroid and added only if the post-merge radius computed from the cluster feature remains within a user-supplied threshold. This keeps the average deviation to each cluster centroid bounded as the cluster grows and preserves a simple interpretation of resolution in physical units. We evaluate mdBIRCH on […]
- by Lyu, B., Lin, J.Biomolecular condensates are viscoelastic, and their mechanical properties are intimately related to their biological functions. However, the connection between microscopic networks formed by intermolecular crosslinks and viscoelasticity is still elusive. Here, we model biomolecular condensates as random crosslinked polymer solutions to elucidate how random connectivity fundamentally alters their viscoelasticity. We decompose the entire solution into multiple tree networks and demonstrate that for networks with size n, their spectra of relaxation rates{lambda} exhibit a power-law scaling pn({lambda}) [~] {lambda}-1/3 with a […]
- by Tam, A. K. Y., Mogilner, A., Oelz, D. B.Bundles of actin filaments with similar positions and orientations commonly occur in cytoskeletal networks. We use mathematical modelling and simulation to investigate how filament turnover and mechanics influence contractility and bundle formation in disordered actomyosin networks. Using a two-dimensional agent-based model for an actomyosin network, we investigate four simplified models for filament turnover: uniform, biased, branching, and treadmilling. With no turnover, over time contractility decreases and bundle formation increases, and networks eventually form stationary patterns that cannot contract. Introducing turnover […]
- by Madsen, N. K., Ziolek, R. M., Kongsgaard, D., Nielsen, C. F., Norlov, A. D., Dolciami, D., Sacher, J. R., Michelsen, K., Acker, M. G., Berglund, N. A., Christensen, M. H., Gronlund, A., Husted, L., Gloriam, D. E., Kooistra, A. J., Zinner, N. T.A great number of drug discovery programs fail due to poor in vivo efficacy and ADMET liabilities. On- and off-target ligand residence times can act as important drivers of these problems. However, the kinetics of ligand-protein residence times has historically been largely overlooked during early-stage drug discovery with a strong focus on binding affinity. While modern experimental techniques have made measuring compound kinetics data more routine, there is a lack of accurate, high-throughput computational techniques to guide compound prioritization by […]
- by Liu, Z. B., Halldorsson, S., Calcraft, T., Calder, L. J., Rosenthal, P. B.Lipid-enveloped viruses, such as influenza virus, assemble by budding from infected cell membranes, packaging internal components including the genome and acquiring an envelope containing surface glycoproteins in the process. Influenza C virus possesses a single surface glycoprotein, the haemagglutinin-esterase-fusion (HEF) protein that forms hexagonal arrays on the membrane envelope and is sufficient for budding of spherical particles. However, a two-dimensional hexagonal lattice cannot completely cover a spherical virus membrane without defects. Using electron cryotomography (cryo-ET), we study the structural arrangement […]
- by Rajput, A. S., Kumar, K., Nishikawa, M., Kumar, K. V.Cell division accomplishes the segregation of genetic material and involves remarkable changes in the cellular geometry culminating in cytokinesis: the cleavage of a mother cell giving rise to two daughter cells. Cytokinesis in animal cells is driven by flows resulting from cortical tension gradients in the actomyosin cortex. Here, we combine a theory for the active geometrodynamics of the cortical surface and quantitative measurements in the C. elegans zygote to reveal the physical principles of cytokinesis. At high activity, we […]
- by Fochler, S., Doran, M. H., Beneke, T., Smith, J., Fort, C., Walker, B. J., Brown, A., Gluenz, E., Wheeler, R. J.Eukaryotic flagella, or motile cilia, are iconic molecular machines whose beating drives cell propulsion and fluid transport across diverse organisms. Beat type and waveform are tailored to function, differing between species and cell types, and individual flagella can switch between beat types. Aberrant beating causes ciliopathies and infertility in humans1 and prevents unicellular parasite transmission2. Eight distinct dynein motor protein complexes bind to axonemal doublet microtubules (DMTs) within flagella and drive beating, yet despite extensive structural analysis3-5, how this machinery […]
- by Arzash, S., Liu, A. J., Manning, M. L.Self-tuning, the ability of disordered systems to develop desired collective behaviors by tuning internal couplings in response to feedback, has recently emerged as a powerful framework for understanding adaptation in amorphous solids, mechanical metamaterials, and electrical networks. These systems can learn desired responses, encode memory, and robustly reorganize under repeated stimuli, much like artificial neural networks but without requiring processors to adjust their weights. Here, we extend this paradigm to morphogenesis and show that the epithelium can be viewed as […]
- by Vasiliauskas, D., Beiter, J., Iyer, S. S., Lombardo, A. T., Mendoza, M. C., Voth, G. A.Ezrin is a peripheral membrane protein that contributes to the organization and stability of cellular membrane structures by reversibly linking the plasma membrane to actin filaments. The formation of this membrane-actin linkage has been experimentally shown to require ezrin N-terminal (FERM) domain binding to PI(4,5)P2 phospholipid-enriched membrane sites and the phosphorylation of the ezrin Cterminal domain (CTD) at residue T567. Collectively, membrane association and T567 phosphorylation are believed to promote separation of the FERM and CTD domains; however, the underlying […]
- by Perets, E. A., Spies, J. A., Cheong, J. H., Shi, L., Asamoto, D. K., Holehouse, A. S., Kim, J. E., Min, W., Neu, J., Yan, E. C. Y.Biomolecular condensates represent unique microenvironments that organize intracellular biology and promote biochemical reactions. However, the biomolecular interactions driving condensate phase separation are often weak, transient, and heterogeneous. Investigating the structural biology and chemical properties of condensate interiors has therefore proven experimentally challenging, often requiring the use of perturbative probes. To overcome this challenge, we combine label-free optical scattering and vibrational spectroscopy approaches spanning ultraviolet, visible, mid-infrared, and terahertz wavelengths with deep-learning-based ensemble prediction of intrinsically disordered protein conformations. Our experimental […]
- by Clavier, A., Shida, T., Gomez-Evain, S., Droemer, M. A., von Hammerstein, F., Holzinger, J., Leuthold, M. M., Schuetz, A.The HBx protein from Hepatitis B virus (HBV) is essential for replication and promotes pathogenicity during chronic infection. HBx hijacks host proteins, reprogramming them to evade antiviral defence. However, the structural basis of recruitment remains largely unknown. The HBx1-120 isoform derives from integration of viral DNA into the host genome and is linked to hepatocellular carcinoma. We present an NMR-based setup to characterize HBx-host protein interactions at residue-level resolution. HBx1-120 is disordered in isolation but undergoes local folding upon binding […]
- by Khaled, M., Johannknecht, L., Palomino-Hernandez, O.TRMT2A has emerged as a disease-modifying target in polyglutamine (PolyQ) models, yet the conformational preferences and allostery of its RNA recognition motif (RRM) remain poorly resolved. Here we combine extensive atomistic molecular dynamics with Markov state modeling (BHMSM), transition path theory, and structure-based pocket analysis to map the conformational landscape of the human TRMT2A RRM. We resolve six metastable states and show that a hydrophobic cluster centered on F92-W134-L133 governs their interconversion. We further identify residues contributing to RNA strand […]
- by Sastokas, A., Ho, W.-C., Schmidlin, K., Brown, P. T., Crossland, P., Shepherd, D. P., Lynch, M. P., Geiler-Samerotte, K.Using a massively parallel evolution platform, we selected Saccharomyces cerevisiae for increased cell size to test how cellular architecture adapts to biophysical constraints. As cells evolved larger size, they became less spherical and showed reduced carrying capacity without changes in maximum growth rate. Optical diffraction tomography revealed that individual cells with greater volume consistently exhibited lower internal density, a relationship that persisted across replicate populations and evolved isolates. The largest cells often contained enlarged vacuoles, suggesting that vacuole expansion may […]
- by Kim, S., Tuma, A., Qin, D., Ryu, Y. J., Kim, D., Abhilash, A., Chintawar, S., Thomas-Holness, C., Fladger, A., Behravesh, E., Zhen, Y., Zhou, Y., Thompson, J. T., Hu, D. L.Bloodworms, Glycera dibranchiata, possess an eversible proboscis that normally remains concealed within their bodies but explosively everts if the worm attacks or burrows. How does the bloodworm evert quickly and reliably? In a series of experiments, we characterize bloodworm kinematics, pressure, and material properties to estimate the criteria for eversion safely without rupture of the proboscis. We predict the proboscis can withstand pressures 50 times higher and bending strains up to three times higher than the respective values observed. We […]
- by Abdo, A., Nada, H., Gabr, M.NOS1AP (CAPON) is an adaptor protein of neuronal nitric oxide synthase (nNOS) correlated with Alzheimers disease progression, making it an attractive yet unexplored therapeutic target. To assess its chemical tractability, we employed affinity selection-mass spectrometry (AS-MS) to screen approximately 10,000 small molecules for CAPON binding, identifying 52 initial hits. These compounds were further evaluated for true binding interactions and potential autofluorescence or quenching effects using the Dianthus platform. Five compounds were selected for quantitative affinity determination by microscale thermophoresis (MST). […]
- by Kuhn, A., Krüger, T., Engstler, M., Fischer, S. C.
- by Pyo, A. G. T., Chan, A., Rosenheim, J., Thakker, C., Bell, L., Nageswaran, G., Byrne, S., Killingley, B., Scobie, D., Kalinova, M., Boyers, A., Catchpole, A., Mann, A., Lindeboom, R. G. H., Nikolic, M. Z., Teichmann, S., Wagstaffe, H., Noursadeghi, M., Chiu, C., Callan, C., Mayer, A., Wingreen, N. S., Chain, B.Quantifying T cell response during primary infection in humans is crucial for understanding adaptive immunity. Leveraging a controlled human challenge to SARS-CoV-2, we characterized antigen-specific T cell response within and across individuals. Notably, individual clones reached similar maximum frequencies despite differences in the timing of their peak expansion. Mathematical modeling showed that this observation is consistent with precursor frequency, but not TCR signal strength, as the source of inter-clonal variability. Single-cell profiling revealed distinct temporal programs for CD4+ and CD8+ […]
- by Li, S., Aristizabal, M. J., Grigoryev, S. A., Panchenko, A. R.Dynamics and physical state of chromatin are crucial in regulating gene expression, DNA replication, and repair. Intrinsically disordered histone tails were previously recognized as key modulators of chromatin states. However, detailed atomistic mechanisms by which histone tail dynamics are associated with chromatin compaction and higher-order chromatin organization remain poorly understood. In this work, we combine extensive all-atom molecular dynamics simulations of tri-nucleosomes with cryo-electron tomography (Cryo-ET) of native nucleosome arrays to investigate histone tail-mediated chromatin folding. Our approach offers distinct […]
- by Wang, Y., Hu, Q., Huang, J.Understanding cellular signaling networks benefits from accurate structural modeling of protein kinases across their different functional states. However, most human kinases lack experimentally determined active-state structures, and existing computational methods often fail to reliably predict catalytically competent conformations. Here, we present a geometry-constrained modeling framework based on AFEXplorer (AFEX) that enables robust prediction of active, ATP- and magnesium-bound states for 436 catalytic kinase domains across the human kinome. By explicitly enforcing key biophysical criteria, AFEX overcomes the template dependence and […]
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