- by Sheikhhassani, V., Wong, F. F. H. K., Bonn, D., Schmit, J. D., Mashaghi, A.Phase-separated biomolecular condensates serve as functional elements of biological cells, as contributors to the formation of protocells in prebiotic systems during early life, and as a distinct form of material with a range of applications. Regulation of condensate mechanochemistry is of critical importance for their functions and properties. Photochemical processes, such as UV-induced chemical changes, are commonly observed in nature and can have both detrimental and constructive impacts on life, and are also readily implemented in engineering applications. However, how […]
- by Galindo, L. J., Takaramoto, S., Nagata, T., Rozenberg, A., Takahashi, H., Beja, O., Inoue, K.Apusomonads are a clade of understudied sediment-dwelling bacterivorous protists sister to Opisthokonta. Recently, apusomonads have been found to show a negative phototactic response to blue light. Here, by screening available apusomonad 'omics data we found genes of a distinct group of microbial rhodopsins, the ApuRs. ApuRs heterologously expressed in mammalian cells absorbed near-UV/violet or blue light, suggesting that ApuRs could be involved in apusomonads' photoavoidance response. Electrophysiological measurements indicate that ApuRs are anion-selective rhodopsin channels which evolved independently of the […]
- by Cylke, A., Banerjee, S.Bacterial populations typically exhibit exponential growth under resource-rich conditions, yet individual cells often deviate from this pattern. Recent work has shown that the elongation rates of Escherichia coli and Caulobacter crescentus increase throughout the cell cycle (super-exponential growth), while Bacillus subtilis displays a mid-cycle minimum (convex growth), and Mycobacterium tuberculosis grows linearly. Here, we develop a single-cell model linking gene expression, proteome allocation, and mass growth to explain these diverse growth trajectories. By calibrating model parameters with experimental data, we […]
- by Raizada, G., Brunel, B., Guillouzouic, J., Le Ferrec, E., Boireau, W., Lesniewska, E., Elie-Caille, C.Extracellular vesicles are heterogenous lipid bound membranous structures released by different cells, showing a great potential to be used as biomarkers. They have been explored by the researchers for their role in the context of environmental toxicity. When exposed to pollutants like polycyclic aromatic hydrocarbons, they undergo surface modification as well as the change of contents in their cargo. Subpopulations of large EVs (lEVs) have shown to contain both damaged and intact mitochondria which is inexorably linked to oxidative stress […]
- by Kidane, A. K., Rosenfeld, J. R., Johnston, J. D., Dubbeldam, C., Paraan, M., Obermeyer, A. C.Understanding the formation of biomolecular condensates in biological systems has proven to be a paradigm shift in our understanding of the subcellular organization of biomacromolecules. From RNA metabolism, stress response mechanisms, and amyloidogenic pathologies, condensates have been implicated to play a role in a myriad of cellular phenomena. Despite their near ubiquity, we still do no wholly understand how the primary sequence of biomolecules influences their biophysical and rheological properties. Here, we aim to understand the impact of primary cationic […]
- by Xu, Y., Huang, J.The hydrogen bonds (H-bonds) between backbone amide and carbonyl groups are fundamental to the stability, structure, and dynamics of proteins. A key feature of such hydrogen bonding interactions is that multiple H-bonds can enhance each other when aligned, as such in the -helix or {beta}-sheet secondary structures. To better understand this cooperative effect, we propose a new physical quantity to evaluate the cooperativity of intermolecular interactions. Using H-bond aligned N-methylacetamide molecules as the model system, we assess the cooperativity of […]
- by Mannsverk, S., Villamil Giraldo, A., Kasson, P. M.Many enveloped viruses enter cells via fusion with the endosomal membrane, raising the question whether entry through the endosomal route confers a fitness advantage over fusion directly at the plasma membrane. We found that influenza A virus fusion at the plasma membrane of A549 cells resulted in a 7.6-fold reduction in productive cell infection, compared to infection through the physiological endosomal route. We hypothesized that this was partially explained by restrictive and permissive membrane factors at the plasma and endosomal […]
- by Schulze, T. K., Blaabjerg, L. M., Cagiada, M., Lindorff-Larsen, K.The increasing availability of data from multiplexed assays of variant effects (MAVEs) enables supervised model training against large quantities of experimental data to learn sequence-function relationships. Variant effect scores from MAVEs can, however, be influenced by the experimental method to create experiment-to-experiment differences in the mapping from molecular level-variant effects to MAVE readout, which presents a challenge for supervised learning across datasets. We here propose a framework for performing supervised learning with MAVE data that takes the influence of the […]
- by Aazmi, O., Aswale, A. R., Saju, L., Chugh, J.The Fused in Sarcoma (FUS) protein, previously implicated in neurodegenerative diseases, contains N- and C-terminal LC-rich regions, a zinc finger motif flanked by two RG-rich regions, and a single RNA-recognition motif (RRM). FUS-RRM monomers undergo amyloid-like aggregation, however, the detailed molecular insights into the fibrillation process are yet to be deciphered. Here, we investigated the conformational heterogeneity of FUS-RRM using NMR relaxation-dispersion experiments. We observed that the monomer (M) exists in a dynamic exchange with an excited state (ES), which […]
- by Ortega, F. M., Hossain, F., Volobouev, V. V., Meloni, G., Torabifard, H., Morcos, F.Protein design is challenging as it requires simultaneous consideration of interconnected factors, such as fold, dynamics, and function. These evolutionary constraints are encoded in protein sequences and can be learned through the latent generative landscape (LGL) framework to predict functional sequences by leveraging evolutionary patterns, enabling exploration of uncharted sequence space. By simulating designed proteins through molecular dynamics (MD), we gain deeper insights into the interdependencies governing structure and dynamics. We present a synergized workflow combining LGL with MD and […]
- by Feng, C., Chu, X.Embryonic stem cells (ESCs) lie at the heart of regenerative medicine and hold significant potential for treating various diseases. Understanding how the transcriptional landscape of ESCs is established during embryogenesis is therefore pivotal for deciphering the origins of life and advancing therapeutic strategies. Given the intrinsic connection between genome structure and function, chromosomal structural organizations during embryogenesis play a vital role in shaping gene expression patterns in ESCs. In this study, we employed a data-driven model and non-equilibrium molecular dynamics […]
- by Dhondt, W., Vanduyfhuys, L., Mehdipour, A. R.An increasing number of ligand-bound membrane protein structures reveal ligand-binding sites on the lipid-exposed surface of the protein within the membrane bilayer. Binding events to such sites have previously been studied using molecular dynamics (MD) simulations and experiments in cases such as calcium-gated potassium channels1 and sodium channels2. The proposed binding mechanism is that these ligands partition into the membrane to gain access to their binding site. What is currently unavailable is what the thermodynamic and kinetic contributions of the […]
- by Willmer, P., Stender, E. G., Ray, K. S., Hundahl, A. C., Marie, R., Jensen, H.Characterizing the kinetics of biomolecular interactions is fundamental for understanding biological mechanisms, developing novel drugs, and optimizing processes in protein engineering. Although modern surface-based methods have advanced our understanding of protein-protein and protein-ligand kinetics, they rely on immobilized samples, preventing the study of interactions under native conditions and leading to an incomplete understanding. We propose a paradigm shift by introducing a method based on flow-induced dispersion analysis to study interaction kinetics while keeping biomolecules in solution, eliminating the need for […]
- by Sharifian, F., Ebrahimi, M., Mehdipour, A. R.1Iron acquisition is a crucial determinant of Mycobacterium tuberculosis (Mtb) survival and pathogenesis, as the bacterium must scavenge iron from the host environment during infection. To achieve this, Mtb synthesizes two structurally distinct siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), efficiently chelate iron and facilitate its uptake. While MBT remains embedded in the membrane due to its hydrophobicity, cMBT is secreted to scavenge extracellular iron. Despite their biological importance, the dynamics of siderophore-membrane interactions remain poorly understood. In this study, we […]
- by Hedglin, M., Norris, J., Rogers, L. O., Young, G., Pytko, K. G., Dannenberg, R. L., Perreault, S., Kaushik, V., Antony, E.The DNA genome is constantly exposed to agents, such as ultraviolet radiation (UVR), that can alter or eliminate its coding properties through covalent modifications of the template bases. Many of these damaging modifications (i.e., lesions) persist into S-phase of the cell cycle where they may stall the canonical DNA replication machinery. In humans, these stalling events are circumvented by one of at least three interconnected DNA damage tolerance (DDT) pathways; translesion DNA synthesis (TLS), Template Switching (TS), and Homology-dependent Recombination […]
- by Lee, J., Chen, L.-F., Gaudin, S., Gupta, K., Spakowitz, A., Boettiger, A.In the last decade, sequencing methods like Hi-C have made it clear the genome is intricately folded, and that this organization contributes significantly to the control of gene expression and thence cell fate and behavior. Single-cell DNA tracing microscopy and polymer physics-based simulations of genome folding have proposed these population-scale patterns arise from motor- driven, heterogeneous movement, rather than stable 3D genomic architecture, implying that motion, rather than structure, is key to understanding genome function. However, tools to directly observe […]
- by Deshmukh, A., Chang, K., Cuala, J., Campos, M. J. H., Mahmood, S., Verma, R., Georgia, S., Loconte, V., White, K. L.Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic {beta}-cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), […]
- by Hu, J., Scheidt, T. J., Thacker, D., Axell, E., Stemme, E., Lapinska, U., Wennmalm, S., Meisl, G., Curk, S., Andreasen, M., Vendruscolo, M., Arosio, P., Saric, A., Schmit, J., Knowles, T., Sparr, E., Linse, S., Michaels, T. C. T., Dear, A. J.The nucleation of amyloid fibrils from monomeric protein, catalyzed by the surface of existing fibrils, is an important driver of many disorders such as Alzheimer's and Parkinson's diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: defects in the fibril core structure generated during their original assembly. We first demonstrate using the specific inhibitor of secondary nucleation, Brichos, that secondary nucleation sites […]
- by Bastien, E., Duprez, G., Delanoë-Ayari, H., Riviere, C., Petrilli, V., Recho, P., Monnier, S.Pyroptosis, an inflammatory form of cell death, is associated with large cell swelling and plasma membrane rupture. Recently, such swelling has been shown to occur in a two steps fashion, but the precise molecular and biophysic mechanisms driving the process remain elusive. We demonstrate through advanced quantitative microscopy that, between the two swelling phases, cell volume stabilizes, while plasma membrane permeability to ions and small molecules is markedly elevated due to the formation of pores. From a biophysical perspective, how […]
- by Gonzalez-Sanabria, N., Contreras, G. F., Rojas, M., Duarte, Y., Gonzalez-Nilo, F. D., Perozo, E., Latorre, R.BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore's open conformation remain unclear. Using cryo-electron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within […]
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