- by Novev, J. K., Lau, J. Y., Marenduzzo, D., Kudla, G.Many RNA molecules function within confined environments, but the effect of confinement on RNA folding remains poorly understood. Proximity ligation experiments reveal altered long-range contacts in confined versus unconfined states, yet they do not explain how spatial constraints give rise to these differences. Here, we develop a physical modeling approach that incorporates proximity ligation data into coarse-grained molecular dynamics simulations to reconstruct RNA 3D structures under confinement. We test our model on the ~11 kb genome of the Zika virus, […]
- by Rai, P., Bergmann, A.Apoptosis in Drosophila is governed by caspases, inhibitor of apoptosis proteins (IAPs), and IAP antagonists. Using AlphaFold3, we modeled full-length 3D structures of the IAP antagonists Reaper, Hid, Grim, Sickle, and Jafrac2, as well as DIAP1 and dBruce, and their binary and higher-order complexes. We uncover a paradoxical role for the N-terminal methionine of Reaper in stabilizing Reaper/Hid complexes and inhibiting DIAP1 binding. Our models reveal that Reaper uniquely engages both BIR1 and BIR2 domains of DIAP1, guided by -helical […]
- by Joffe, A. M., Chorlay, A., Huzar, J., Hasnain, J., Geissler, P. L., Fletcher, D. A.Macrophages recognize and phagocytose opsonized target cells, including those coated with IgG antibodies. This process relies on binding of IgG to Fc{gamma} receptors (Fc{gamma}R) expressed on the macrophage surface, resulting in formation of a phagocytic synapse. Since the surface of both macrophages and target cells are densely packed with macromolecules of diverse sizes, most of which are not directly involved in phagocytic signaling, it is possible for tall 'bystander' proteins to sterically interfere with Fc{gamma}R engagement. Here, we use cell-like […]
- by Qadri, A. H., Trapathi, R. M., Faheem, I., Meshram, S., Reddem,, E. R., Ramachandran, R., Pasupulati, A. k.Introduction: The podocyte slit diaphragm (SD) is a complex filtration unit localized to the blood and urine interface and governs the glomerular selectivity. However, the greater details of the SD composition and the mechanism of assembly of the SD protein as a macromolecular complex remain elusive. CD2 associated protein (CD2AP) serves as a central scaffold within the SD, and mutations in CD2AP are strongly associated with nephrotic syndrome (NS) and focal segmental glomerulosclerosis (FSGS). However, the mechanisms by which such […]
- by Karlsson, E., Ygland, I., Jansen, A., Plumley, J., Lindahl, E., Howard, R. J., Hess, B.Pentameric ligand-gated ion channels (pLGICs) are key mediators of electrochemical signal transduction in various organisms. Like many proteins involved in cellular signaling, they are modulated by a variety of environmental factors including pH and small molecules. However, the molecular mechanisms underlying pLGIC activation and modulation remain unclear. A promising model system in this family is the bacterial ion channel sTeLIC, which can be activated by alkaline pH, and for which we recently determined structures in multiple functional states. However, protonation […]
- by Alcalde Cuesta, F., Guerberoff, G. R., Lozano Rojo, A.AO_SCPLOWBSTRACTC_SCPLOWIn this paper, we study the absorption and fixation times for evolutionary processes on graphs, under different updating rules. While in Moran process a single neighbour is randomly chosen to be replaced, in proliferation processes other neighbours can be replaced using Bernoulli or binomial draws depending on 0 pc or p < pc. We clarify the role of symmetries for computing the fixation time in Moran process. We show that the Maruyama-Kimura symmetry depend on the graph structure induced in […]
- by Peterle, D., Yan, N. L., Klimtchuk, E. S., Wales, T. E., Gursky, O., Kelly, J. W., Engen, J. R., Morgan, G. J.Immunoglobulin light chains, a component of antibodies, can misfold and aggregate to cause systemic AL amyloidosis. Aggregation, including amyloid fibril formation, requires unfolding of the full-length light chain from its native state, and in most cases aberrant proteolysis. Small molecules that bind to the native state of light chains to stabilize them against conformational excursions and proteolysis are under development as drug candidates for AL amyloidosis. Since each patient has a unique light chain sequence, a challenge for candidate stabilizer […]
- by Uddin, A., Serebryany, E.Intrinsically disordered proteins can aggregate in many distinct conformations (polymorphs). Polymorphs are a striking example of fold-switching: one primary structure able to form distinct tertiary structures. Distinct polymorphs can yield distinct molecular, cellular, and disease phenotypes. Disulfide crosslinks canalize disordered proteins into distinct regions of the conformational landscape, even if the monomer remains disordered. Human -synuclein is a disordered, natively Cys-free protein involved in synaptic transmission. Its amyloid aggregation is implicated in Parkinsons disease and other synucleinopathies. Recent cryo-EM fibril […]
- by Walsh-Korb, Z., Boult, S., Vanella, R., Ali Tunio, I., Li, J., Doffini, V., Ul Ahad, I., Nash, M. A.The catch bond complex between serine-aspartate repeat protein G (SdrG) from Staphylococcus epidermidis and the beta chain of fibrinogen (Fg{beta}) exhibits two distinct rupture populations when dissociated under tensile force. Such complexes present exciting possibilities for developing dynamic biomaterials due to their unique response to shear force. However, the environmental responsiveness of this complex and its influence on adhesion behaviour in multi-valent systems remain underexplored. Using AFM-single molecule force spectroscopy (AFM-SMFS) and spinning disk adhesion (SDA) assays, we examined how […]
- by Bonini, A., Lu, C., Mantovanelli, L., Versloot, R. C. A., Jansen, A., O Connell Stack, P., Tsousi, V., Knecht, P., Lang, K., Heron, A., Maglia, G.Nanopore-based technologies show promise in single-molecule protein sequencing. By using an unfoldase and a nanopore with enhanced electroosmotic flow, here we show the continuous identification of generic proteins during single nanopore passes. This approach enables the recording of differences in charge and size from single amino acid substitutions compared to reference signals, paving the way for single-molecule protein sequencing and high-throughput proteomics.
- by Rastrygina, V. A., Deryusheva, E. I., Kazakov, A. S., Sokolov, A. S., Permyakova, M. E., Litus, E. A., Uversky, V. N., Permyakov, E. A., Permyakov, S. E.Tumor Necrosis Factor Superfamily (TNFSF) comprises 20 members of membrane/soluble signaling proteins regulating cell survival, cell proliferation/differentiation, and innate/adaptive immunity. Targeting signaling of TNFSF members is used clinically to treat several autoimmune and oncological diseases, and bone loss. They and their cognate receptors are in clinical trials as targets for treatment of autoimmune, inflammatory, oncological and other diseases. Recently, some representatives of S100 family of pleiotropic calcium-binding proteins were shown to interact with TNFSF members TNF and TRAIL, thereby suppressing […]
- by Muguet, I., Bourrier, D., Calmon, P.-F., Lapeze, P., Joseph, P., Delarue, M.Polydimethylsiloxane (PDMS) is widely used in academic microfluidics due to its favorable biocompatible properties and compatibility with soft lithography. Moreover, the recent developments of reconfigurable microfluidics rely on the microfabrication of sliding elements, which are 3D objects insertable inside a microfluidic chip to provide a given function. However, the complexity of microfluidic device geometries or sliding elements remains largely limited by the traditional microfabrication methods such as, among others, on SU-8 photolithography or dry epoxy films. Such methods are suited […]
- by Alvarez, L., Garrone, N. A., Claron, M., Schweimer, K., Glavina, J., Will, D., Sehr, P., Lewis, J., Gibson, T. J., Sanchez, I. E., Hennig, J., Chemes, L. B.Intrinsically disordered protein regions (IDRs) mediate key steps in cellular signaling but the nature of the energy barriers crossed by IDRs upon association and the energetic features of the transition state ensemble (TSE) for binding remain elusive. Short linear motifs (SLiMs) are small functional units found within IDRs that fold upon binding to globular domains. Here, we use the LxCxE SLiM from the human papillomavirus E7 protein (LxCxEWT) binding to the retinoblastoma (Rb) protein as a minimal model system for […]
- by Kenanoglu, C. U., Wiertlewski, M., Vardar, Y.Electrostatic actuation enables programmable tactile feedback on touchscreens by modulating finger-surface friction through an oscillating electric field. Previous studies have attributed this modulation to adhesion, where increased real contact area enhances friction. However, adhesion alone cannot explain the frequency-dependent behavior observed under oscillation, indicating a role of vibration-driven fingertip dynamics. Here, finger-glass contact is directly visualized and quantified in 10 participants using frustrated total internal reflection, providing the first time-resolved measurements of real contact area modulation synchronized with normal and […]
- by Muzata, D., Sanyal, D., Pandey, D., Chakraborti, S., Uversky, V. N., Upadhyay, P., Chowdhury, S.Antifolate resistance in P. falciparum dihydrofolate reductase remains a major challenge for malaria control. To understand how this enzyme preserves function under antifolate selection, we developed PfPATH, a computational framework that integrates mutational fitness measurements, evolutionary interactions, and structural information to map plausible adaptive trajectories. PfPATH adaptive walks reveal that only a small subset of residues forms a constrained adaptive ridge that guides evolution. Most resistance mutations are harmful on their own and only become viable when supported by stabilizing […]
- by Vanhille Campos, C., Krstic, M., Baum, B., Munoz-Basagoiti, M., Saric, A.Cytomotive filaments, a prominent class of cytoskeletal polymers comprising the actin and tubulin families, combine directional growth with monomer turnover to perform essential cellular functions. While the functional role of turnover is becoming increasingly clear, how these filaments dynamically self-assemble using a single monomer type remains an open question. Here we exploit physical modelling in combination with genetic algorithms to elucidate the design principles that drive monomer self-assembly into treadmilling filaments – polar filaments that grow on one end and […]
- by Karubiu, W., Kullmann, R., Krummhaar, M., Roth, C., Weikl, T. R.The aspartic protease plasmepsin X (PMX) of the parasite Plasmodium is a promising drug target for novel malaria therapies. Two potent inhibitors of PMX are WM382 and WM4, which both include a guanidinium group that is in contact with the two catalytic aspartates of PMX in the bound complexes. In structural representations of the inhibitors, the guanidinium group is typically depicted as uncharged. However, pKa predictions with standard tools presented in this article indicate that the guanidinium groups of WM382 […]
- by Tang, J., Chu, X.Chromatin folding is regulated by multivalent protein complexes and condensates, yet how the multivalent binding quantitatively controls chromatin compaction, domain organization, and cell-to-cell heterogeneity remains unresolved. Here we develop the Chromatin-associated Protein Complex Maximum Entropy Model (CPC-MEM), a data-driven, physics-based polymer framework in which Hi-C contacts are realized through an explicit, finite pool of diffusing chromatin-associated protein complexes (CPCs) with prescribed CPC-chromatin interaction valency. When fitted to Hi-C, CPC-MEM generates chromatin structural ensembles that simultaneously reproduce population-averaged contact maps and […]
- by Bhakat, S.Here, we introduce a workflow that combines BioEmu generated conformational ensemble with physics based molecular simulations and Markov State Model to capture biomolecular conformational dynamics. BioEmu augmented molecular simulation approach captures active-to-inactive transitions in serine-threonine kinases and resolves how disease-causing mutations lead to population shifts among distinct metastable states. Compared to AlphaFold2 based reduced multiple sequence alignment (rMSA-AF2) approaches, BioEmu generated ensemble covers a broader conformational space and, when integrated with molecular dynamics simulations, enable Boltzmann weighted sampling of rare […]
- by Bose, S., Aly, A., Karamyan, V. T., Orlando, B. J., Dickson, A.Neurolysin (Nln) is an M3 metallopeptidase that regulates neuropeptide concentration in the central nervous system. It has emerged as a therapeutic target for mitigating post-ischemic injury by hydrolyzing and inactivating several neuropeptides. It has been recently shown that small molecule activators, such as pyridine piperazine (Py-Pip) derivatives, can enhance Nln catalytic activity, facilitating hydrolysis of Nln substrate peptides. However, binding sites of these molecules and the mechanism of action remain unclear due to the dynamic nature of Nln. Here, we […]
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