- by Li, L., Pohl, L., Hutloff, A., Niethammer, B., Thurley, K.Cytokine-mediated communication is a central mechanism by which immune cells coordinate activation, differentiation and proliferation. While mechanistic reaction-diffusion models provide detailed descriptions of cytokine secretion and uptake at the cellular scale, their computational cost limits their applicability to large and densely packed cell populations. Previously employed approximations of cytokine diffusion fields rely on assumptions that neglect the influence of cellular geometry and volume exclusion. In this work, we study a macroscopic description of cytokine diffusion and reaction dynamics based on […]
- by Juarez-Contreras, I., Kim, H., Budin, I.A hallmark of eukaryotic membranes is the pairing of lineage-specific sterols with characteristic sphingolipid species. Mammalian cell membranes are enriched in both cholesterol and long-chain sphingolipids like sphingomyelin, whereas fungi synthesize ergosterol and very long-chain sphingolipids with sugar-containing head groups. It has been proposed that these two lipid classes co-evolved to support membrane structure and organization. Here we investigated how sterol structure and sphingolipid chain length together control membrane order and phase behavior. In the yeast Saccharomyces cerevisiae, loss of […]
- by Tan, T., Bergman, M., Hall, C. K., You, F.Microplastic (MP) pollution, which is present in the ecosystem in vast quantities, adversely affects human health and the environment, making it imperative to develop methods for its mitigation. The challenge of detecting or capturing MPs could potentially be addressed using plastic-binding peptides (PBPs). The ideal PBP for MP remediation would not only bind strongly to plastic, but also have other properties such as high solubility in water or great binding specificity to a certain plastic. However, the scarcity or absence […]
- by Kant, S., Maity, A., Masipeddi, S., Bhagat, M. R., Bahadur, R. P.A crucial step in early spliceosome assembly is the interaction between splicing factor 3A1 (SF3A1) of U2 snRNP and stem-loop 4 (SL4) of U1 snRNA. This interaction facilitates the spatial alignment of the 5' and the 3' splice sites, leading to the formation of the pre-spliceosomal A complex. In this study, we investigate the structural and dynamic basis of non-canonical recognition between ubiquitin-like domain (ULD) of SF3A1 and SL4 of U1 snRNA. Extensive all-atom molecular dynamics simulations reveal a dual […]
- The cytoplasmic lattice in mammalian eggs sequesters ubiquitination machinery and tubulin in reserveby Li, Y., Zheng, W., Leem, J., Wu, C., Tang, S., Mogessie, B., Xiong, Y.The cytoplasmic lattice (CPL) in mammalian eggs is essential for early embryonic development, but its molecular components, structural organization, and functional capacity have remained elusive. Here, using cryo-electron microscopy, we show that the CPL filament in mouse eggs contains repeating units with a periodicity of ~37 nm, and determine its high-resolution, native structure and complete subunit composition. The CPL architecture organizes maternal-effect proteins, ubiquitination machinery, and tubulin into a highly structured reservoir. Maternal-effect proteins form the scaffold of the CPL […]
- by Kupriianova, T., Schwarzer, T., Thalacker, T., Defelipe, L., Etzold, S., Kulow, F., Pahl, V., Goyal, S., Nguyen, V., Zimmermann, M., Guse, A., Cambronne, X. A., Tidow, H., Fliegert, R., Garcia-Alai, M. M.TRPM2 is a Calcium permeable cation channel activated by ADP-ribose (ADPR) and oxidative stress, yet the relative contributions of its two nucleotide-binding domains, MHR1/2 and NUDT9H, remain incompletely understood. Here, we quantitatively determine the affinities of the isolated human TRPM2 MHR1/2 and NUDT9H domains for ADPR, 2-deoxy-dADPR (dADPR), and 8-Br-cADPR using biophysical approaches. The MHR1/2 domain binds ADPR with high affinity (Kd; 0.5 uM), whereas the NUDT9H domain displays substantially lower affinity (Kd; 192 uM), revealing a difference of nearly […]
- by Khan, H., Garcia-Galindo, P., Ahnert, S. E., Dingle, K.A morphospace is an abstract space of theoretically possible biological traits, shapes, or property values. It is interesting to explore which parts of a morphospace life occupies, as compared to those parts which could be occupied, but are not. Comparing random and natural non-coding (nc) RNA secondary structures is an established approach to studying morphospace occupation for RNA structures. Most earlier studies have focused on the minimum free energy (MFE) structure, while relatively few have looked at the Boltzmann distribution, […]
- by Yin, S., Mi, X., Barrett, S. E., Mitchell, D. A., Shukla, D.Lasso peptides adopt a distinctive rotaxane conformation, yet the principles governing the folding of this kinetically trapped structure have remained elusive. Here, we integrated extensive molecular dynamics simulations and deep learning to elucidate the de novo folding mechanism of 20 lasso peptides lacking secondary post-translational modifications. We constructed Multi-Ensemble Markov Models for each lasso peptide and uncovered a universal uphill folding landscape with spontaneous folding probabilities consistently below 0.8%. Loop stability strongly correlated with folding propensity, and targeted experiments further […]
- by Chambers, O., Cadby, A. J.In contemporary bio-imaging-based research, computer-based assessment is becoming crucial for the characterisation of biological structures, as it minimises the need for time-consuming human annotation, which is prone to human error. Furthermore, it allows for the use of optical techniques that use lower photon intensities, thereby reducing reliance on high-intensity excitation and mitigating adverse effects on their activities. This study details the development and evaluation of sophisticated deep-learning models for amoeba detection using phase-contrast imaging. Using a single-class annotated dataset comprising […]
- by Wu, Y., Shinobu, A.Protein kinases regulate signaling by recognizing short sequence motifs, and how these motifs bind influences both specificity and therapeutic strategies that target kinase pathways. Peptide-based inhibitors that engage substrate-recognition regions are attracting interest, but designing them requires an understanding of how a flexible peptide approaches and settles into the bound pose. Traditional studies have focused on the bound pose and affinities, whereas the steps that link the initial encounter with the bound pose have been explored less thoroughly because the […]
- by Xu, F.-Y., Wang, Y.-X.Despite the increased water content in fibrotic livers, numerous studies reported a decrease in ADC (apparent diffusion coefficient) in liver fibrosis. We argue that the ADC decrease in fibrotic livers is due to the T2 shine-through of ADC, as the longer T2 in liver fibrosis leads to less signal decay between the low and high b-value images. The metric slow diffusion coefficient (SDC) was proposed to mitigate the difficulties associated with this T2 shine-through of ADC. This study calculated ADC […]
- by BAHO VITA, H., Welegebriel, D. F.This study investigates closed kinematic chain biomechanics in cycling with a focus on knee joint loading. Data from 16 cyclists collected on a standardized ergometer were analyzed in OpenSim using inverse dynamics, static optimization, and joint reaction analysis. To keep the pipeline consistent across all subjects, the report summarizes right-knee outputs over a steady-state interval between 120 and 124 s. Peak knee joint moments ranged from 15.79 to 44.85 Nm (mean 30.49 +/- 7.66 Nm), while peak resultant knee reaction […]
- by Liu, T., Huang, S., Li, W., Wang, P., Song, J., Liu, J., Zhang, M., Sun, B.Predicting protein-protein interaction affinities from structural data remains a challenge. Although binding funnel theory describes the formation of native complexes, the topography of the funnel bottom and its influence on affinity are often overlooked. Using nanobody-antigen complexes as model systems, we identified two series of nanobodies that adopt nearly identical binding poses toward their respective antigens yet exhibit diverse affinities. These series correspond to two distinct binding paradigms: a static paradigm in which affinity is accurately ranked by Rosetta scoring […]
- by Pedraza, E., Tejedor, A. R., S. Zorita, A., Collepardo-Guevara, R., De Sancho, D., Llombart, P., Rene Espinosa, J.Biomolecular condensates formed by complex coacervation of highly charged proteins provide a powerful framework to understand how microscopic interactions give rise to macroscopic material properties. Atomistic molecular dynamics simulations provide detailed insights but remain limited in accesing the spatio-temporal scales relevant for condensate behavior. Here, we use the residue-level coarse-grained Mpipi-Recharged model to investigate condensates formed by ProT and positively charged partners, including histone H1, protamine, poly-lysine, and poly-arginine. Material properties, in this context, provide a stringent experimental benchamark for […]
- Cost-function Optimized Maximal Overlap Drift Estimation for Single Molecule Localization Microscopyby Reinkensmeier, L., Aufmkolk, S., Farabella, I., Egner, A., Bates, M.Single-molecule localization microscopy (SMLM) methods enable fluorescence imaging of biological specimens with nanometer-scale resolution. Although fluorophore localization precision is theoretically limited only by photon statistics, in practice the resolution of SMLM images is often degraded by physical drift of the sample and/or the microscope during data acquisition. At present, correcting this effect requires either specialized stabilization systems or computationally intensive post-processing, and established drift correction algorithms based on image cross-correlation suffer from limited temporal resolution. In this study we introduce […]
- by Schmidt, L., de Groot, B.Sodium ions (Na+) are key modulators of G-protein coupled receptor (GPCR) function, yet their mechanistic role remains incompletely understood. Here, we reveal a novel mode of Na+-mediated inactivation in the dopamine D2 receptor (DRD2), where Na+ reshapes long-range allosteric coupling networks and disrupts a continuous internal water column essential for activation. Using extensive molecular dynamics simulations and alchemical free energy calculations, we show that Na+ induces inactive-like residue interactions in the active state and triggers the formation of a distinct […]
- by Lee, B. H., Scaramozzino, D., Piticchio, S., Orellana, L.Disease-related missense mutations reshape protein conformational energy landscapes, thereby altering biological function. However, mechanistically linking sequence variation to changes in conformational dynamics remains challenging for both experimental and computational approaches. Here, we introduce an internal-coordinate-based, essential-dynamics-refined elastic network model (ICed-ENM) that improves the physical fidelity of normal modes while capturing subtle mutation-induced side-chain effects and preserving computational efficiency. By constraining bond-length and bond-angle fluctuations and refining mode subspaces against experimentally observed collective motions, ICed-ENM provides a stable, structure-encoded description of […]
- by Brauburger, S., Kraus, B. K., Walther, T., Abele, T., Goepfrich, K., Schwarz, U. S.It is an essential element of mechanobiology to measure the forces of biological cells. In microparticle traction force microscopy, they are inferred from the deformation of elastic microparticles. Two complementary variants have been introduced before: the volume method, which reconstructs surface stresses from the displacements of fiducial markers embedded inside the particles, and the surface method, which infers stresses directly from the deformation of the particle surface. However, a systematic comparison of the two methods has been lacking. Here, we […]
- by Salari, V., Seshan, V., Rishabh, R., Oblak, D., Simon, C.Ultraweak photon emission is the spontaneous emission of extremely low levels of light from a broad range of biological systems. Recent studies have reported that UPE measured extracranially can serve as a potential non-invasive biomarker of brain activity. Here, we show that this interpretation suffers from serious problems. First, when observed under properly dark conditions, the UPE from the head is much weaker than what is reported in certain papers on 'brain UPE' from human heads. Signals detected in these […]
- by Geary, C., Tran, M. P., Poppleton, E., Taskina, A., Göpfrich, K.Constructing complex three-dimensional RNA nanostructures requires precise molecular connectors for controlled self-assembly. Existing RNA-RNA connectors, such as kissing loops, are restricted to coaxial, end-to-end joining, limiting the range of accessible geometries. Here, we introduce the alpha kissing loop (alphaKL), a compact, sequence-programmable RNA connector that enables edge-to-edge helix association.The alphaKL combines a four-nucleotide kissing loop with minor- and major-groove triplex interactions that pre-organize an $alpha$-shaped conformation compatible with cotranscriptional folding. Embedded into RNA origami tiles, alphaKLs drive multivalent assembly into […]
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