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Assessing AF2's ability to predict structural ensembles of proteins bioRxiv. Biophys. Pub Date : 2024-04-17 Jakob R Riccabona, Fabian C Spoendlin, Anna-Lena M Fischer, Johannes R Loeffler, Patrick K Quoika, Timothy P Jenkins, James A Ferguson, Eva Smorodina, Andreas Hougaard Laustsen, Victor Greiff, Stefano Forli, Andrew Ward, Charlotte Deane, Monica Lisa Fernandez-Quintero
Recent breakthroughs in protein structure prediction have enhanced the precision and speed at which protein configurations can be determined, setting new benchmarks for accuracy and efficiency in the field. However, the fundamental mechanisms of biological processes at a molecular level are often connected to conformational changes of proteins. Molecular dynamics (MD) simulations serve as a crucial
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Context-dependent structure formation of RNA hairpin motifs bioRxiv. Biophys. Pub Date : 2024-04-17 Veronika Bukina, Anze Bozic
Many functions of ribonucleic acid (RNA) rely on its ability to assume specific sequence-structure motifs. Packaging signals of some RNA viruses - hairpin motifs that interact with capsid proteins and drive self-assembly - are a prominent example. While interaction specificity demands the formation of stable motifs, they remain a small part of a much larger genomic RNA. An underexplored question is
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Planar Optical Tweezer Trap (2D-LOT) System Realized by Light Sheet Illumination & Orthogonal Widefield Detection bioRxiv. Biophys. Pub Date : 2024-04-17 Neptune Baro, Partha Pratim Mondal
We report the realization of the first planar optical tweezer trap system by a sheet of light. To visualize the trapping of the target object (dielectric bead or live cell) in a plane, an orthogonal widefield detection is employed. The planar / two-dimensional lightsheet optical tweezer (2D-LOT) sub-system is realized in an inverted microscopy mode with illumination from the bottom. A 1064 nm laser
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Bi-directional allosteric pathway in NMDA receptor activation and modulation bioRxiv. Biophys. Pub Date : 2024-04-17 Paula Bender, Subhajit Chakraborty, Ryan Durham, Vladimir Berka, Elisa CarrilloFlores, Vasanthi Jayaraman
N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational
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Design of antigens to present a tumor-specific cryptic epitope bioRxiv. Biophys. Pub Date : 2024-04-17 Huafeng Xu, Timothy Palpant, Qi Wang, David E. Shaw
In many cancers, the epidermal growth factor receptor (EGFR) gene is amplified, mutated, or both. The monoclonal antibody mAb806 binds selectively to cancer cells that overexpress EGFR or express the truncated mutant EGFRvIII, but not to normal cells. This suggests that a promising avenue for developing cancer vaccines may be to design antigens that elicit mAb806-like antibodies. In this study, we
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Growth couples temporal and spatial fluctuations of tissue properties during morphogenesis bioRxiv. Biophys. Pub Date : 2024-04-17 Antoine Fruleux, Lilan Hong, Adrienne H. K. Roeder, Chun-Biu Li, Arezki Boudaoud
Living tissues display fluctuations -- random spatial and temporal variations of tissue properties around their reference values -- at multiple scales. It is believed that such fluctuations may enable tissues to sense their state or their size. Recent theoretical studies developed specific models of fluctuations in growing tissues and predicted that fluctuations of growth show long-range correlations
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Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF inhibitors bioRxiv. Biophys. Pub Date : 2024-04-17 Joseph Clayton, Aarion Romany, Evangelia Matenoglou, Evripidis Gavathiotis, Poulikos I. Poulikakos, Jana Shen
Aberrant signaling of BRAF(V600E) is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAF(V600E) and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and
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Wide Transition-State Ensemble as Key Component for Enzyme Catalysis bioRxiv. Biophys. Pub Date : 2024-04-17 Gabriel Ernesto Jara, Francesco Pontiggia, Renee Otten, Roman V Agafonov, Marcelo Adrian Martí, Dorothee Kern
Transition-state theory has provided the theoretical framework to explain the enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles of conformations, unique transition states would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied the nature of the enzymatic transition state for the phosphoryl-transfer
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Structure and function of an intermediate GPCR-G protein complex bioRxiv. Biophys. Pub Date : 2024-04-17 Maxine Bi, Xudong Wang, Jinan Wang, Jun Xu, Wenkai Sun, Victtor Ayo Adediwura, Yinglong Miao, Yifan Cheng, Libin Ye
Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ structures, these snapshots primarily capture the fully activated end-state complex. Consequently, a comprehensive understanding of the conformational transitions during GPCR activation and the roles of intermediate GPCR-G protein complexes in signaling
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A chaperone and a heat-resistant obscure (Hero) protein mediates conformational extension and aggregation suppression of TDP-43 bioRxiv. Biophys. Pub Date : 2024-04-17 Andy Y.W. Lam, Kotaro Tsuboyama, Hisashi Tadakuma, Yukihide Tomari
The misfolding and aggregation of proteins are characteristic features in the progression of neurodegenerative diseases. While molecular chaperones are well-known suppressors of these aberrant events, we recently reported that a widespread family of heat-resistant obscure (Hero) proteins may also play a similar role. However, how such electrostatically charged intrinsically disordered proteins protect
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GōMartini 3: From large conformational changes in proteins to environmental bias corrections bioRxiv. Biophys. Pub Date : 2024-04-16 Paulo C. T. Souza, Luis P. Borges Araujo, Chris Brasnett, Rodrigo A. Moreira, Fabian Grunewald, Peter Park, Liguo Wang, Hafez Razmazma, Ana C. Borges-Araujo, Luis F. Cofas-Vargas, Luca Monticelli, Raul Mera-Adasme, Manuel N. Melo, Sangwook Wu, Siewert J. Marrink, Adolfo B. Poma, Sebastian Thallmair
Coarse-grained modeling has become an important tool to supplement experimental measurements, allowing access to spatio-temporal scales beyond all-atom based approaches. The GōMartini model combines structure- and physics-based coarse-grained approaches, balancing computational efficiency and accurate representation of protein dynamics with the capabilities of studying proteins in different biological
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Efficient calculation of orientation-dependent lipid dynamics from membrane simulations bioRxiv. Biophys. Pub Date : 2024-04-15 Milka Doktorova, George Khelashvili, Michael F Brown
Molecular dynamics simulations of lipid membranes have become increasingly impactful in biophysics because they offer atomistic resolution of structural fluctuations in relation to their functional outputs. Yet quantitative characterization of multiscale processes is a formidable challenge due to the distribution of motions that evade analysis of discrete simulation data. Here we investigate the efficient
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Biophysical characterization of high-confidence, small human proteins bioRxiv. Biophys. Pub Date : 2024-04-15 A. M. Whited, Irwin Jungreis, Jeffre Allen, Christina Cleveland, Jonathan M Mudge, Manolis Kellis, John Rinn, Loren E Hough
Significant efforts have been made to characterize the biophysical properties of proteins. Small proteins have received less attention because their annotation has historically been less reliable. However, recent improvements in sequencing, proteomics, and bioinformatics techniques have led to the high-confidence annotation of small open reading frames (smORFs) that encode for functional proteins,
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Unlocking TAS2R14 activation through intricate multi-ligand binding networks bioRxiv. Biophys. Pub Date : 2024-04-15 Xiaolong Hu, Weizhen Ao, Mingxin Gao, Lijie Wu, Yuan Pei, Shenhui Liu, Qianqian Sun, Junlin Liu, Longquan Jiang, Yiran Wu, Xin Wang, Yan Li, Qiwen Tan, Jie Cheng, Fan Yang, Chi Yang, Jinpeng Sun, Tian Hua, Zhijie Liu
Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1-3. In addition, TAS2R14 has broad expression in non-gustatory tissues, suggesting its important roles in selective physiological processes and therapeutic potential4. Here, we present cryo-electron microcopy structures of TAS2R14
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Selective phase separation of transcription factors is driven by orthogonal molecular grammar bioRxiv. Biophys. Pub Date : 2024-04-15 Mark D Driver, Patrick R Onck
Protein production is critically dependent on gene transcription rates, which are regulated by RNA polymerase and a large collection of transcription factors (TFs). Previous studies identified the formation of super enhancer regions where increased transcriptional activity is observed. This has been linked to phase separation, in which the differential condensation behaviour of separate TF families
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In situ investigation of extracellular vesicles in viscous formulations: interplay of nanoparticle transport and nanorheology through interferometric light microscopy analysis bioRxiv. Biophys. Pub Date : 2024-04-15 Lucile Alexandre, Anastasiia DUBROVA, Aruna KUNDURU, Marie BERGER, Imane BOUCENNA, Florence GAZEAU, Amanda Karine Andriola SILVA, Stéphanie MANGENOT, Kelly AUBERTIN
While extracellular vesicles (EVs) demonstrate growing potential as innovative therapeutics in diverse medical context (cancer, regenerative medicine, etc.) or as naturally circulant diagnostic / prognostic probes, their physical properties (size, transport, etc.) remains a critical concern. Here, we introduce a pipeline that relies on interferometric light microscopy (ILM) for measuring not only nanoparticle
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Molecular Dynamics Trajectory Analysis of Permeation (MDTAP): A tool to analyze permeation events across membrane proteins bioRxiv. Biophys. Pub Date : 2024-04-15 Raghuvamsi Venkata Palur, Sruthi Sundaresan, Thenmalarchelvi Rathinavelan
Background and Objective Molecular dynamics (MD) simulations are indispensable and versatile in capturing the time-dependent conformational changes of biomolecules to shed light on the concomitant biological processes. MD is used to provide critical mechanistic insights into the transportation of solvent/solute/drug molecules across protein channels embedded in a membrane bilayer. The huge size and
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Confinement in fibrous environments positions and orients mitotic spindles bioRxiv. Biophys. Pub Date : 2024-04-15 Apurba Sarkar, Aniket Jana, Atharva Agashe, Ji Wang, Rakesh Kapania, Nir S. Gov, Jennifer G. DeLuca, Raja Paul, Amrinder S. Nain
Accurate positioning of the mitotic spindle within the rounded cell body is critical to physiological maintenance. Adherent mitotic cells encounter confinement from neighboring cells or the extracellular matrix (ECM), which can cause rotation of mitotic spindles and, consequently, titling of the metaphase plate (MP). To understand the positioning and orientation of mitotic spindles under confinement
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Diffusion-limited cytokine signaling in T cell populations bioRxiv. Biophys. Pub Date : 2024-04-15 Patrick Brunner, Lukas Kiwitz, Lisa Li, Kevin Thurley
Effective immune-cell responses depend on collective decision-making mediated by diffusible intercellular signaling proteins called cytokines. Here, we designed a spatio-temporal modeling framework and a precise finite-element simulation setup, to systematically investigate the origin and consequences of spatially inhomogeneous cytokine distributions in lymphoid tissues. We found that such inhomogeneities
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Compliant DNA Origami Nanoactuators as Size-Selective Nanopores bioRxiv. Biophys. Pub Date : 2024-04-15 Ze Yu, Anna V. Baptist, Susanne C. M. Reinhardt, Eva Bertosin, Cees Dekker, Ralf Jungmann, Amelie Heuer-Jungemann, Sabina Caneva
Biological nanopores crucially control the import and export of biomolecules across lipid membranes in cells. They have found widespread use in biophysics and biotechnology, where their typically narrow, fixed diameters enable selective transport of ions and small molecules as well as DNA and peptides for sequencing applications. Yet, due to their small channel sizes, they preclude the passage of large
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Traction Force Microscopy with DNA FluoroCubes bioRxiv. Biophys. Pub Date : 2024-04-15 Armina Mortazavi, Jianfei Jiang, Philip Laric, Dominic Helmerich, Rick Seifert, Markus Sauer, Benedikt Sabass
From cell differentiation to morphogenesis and cell migration, a multitude of processes are coordinated by mechanical forces that cells generate. Among diverse techniques to assess the mechanical properties of the cell, traction force microscopy (TFM) has emerged as one of the most popular methods for quantifying cell-generated stresses. Standard TFM procedures rely on fiducial markers in the extracellular
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Improved prediction of stabilizing mutations in proteins by incorporation of mutational effects on ligand binding bioRxiv. Biophys. Pub Date : 2024-04-15 Srivarshini Ganesan, Nidhi Mittal, Akash Bhat, Rachna S Adiga, Ananthakrishnan Ganesan, Deepesh Nagarajan, Raghavan Varadarajan
While many computational methods accurately predict destabilizing mutations, identifying stabilizing mutations has remained a challenge, due to their relative rarity. We tested DeltaDeltaG0 predictions from computational predictors such as Rosetta, ThermoMPNN, RaSP, and DeepDDG, using eighty-two mutants of the bacterial toxin CcdB as a test case. On this dataset, the best computational predictor is
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Structural and Dynamic Insights into the Biased Signaling Mechanism of the Human Kappa Opioid Receptor bioRxiv. Biophys. Pub Date : 2024-04-15 Chiyo Suno-Ikeda, Ryo Nishikawa, Riko Suzuki, Seiya Iwata, Tomoyo Takai, Takaya Ogura, Mika Hirose, Akitoshi Inoue, Eri Asai, Ryoji Kise, Yukihiko Sugita, Takayuki Kato, Hiroshi Nagase, Tsuyoshi Saito, Kota Katayama, Asuka Inoue, Hideki Kandori, Takuya Kobayashi, Ryoji Suno
The κ–opioid receptor (KOR) is a member of the G protein coupled receptor (GPCR) family, responsible for modulating cellular responses through transducers such as G proteins and arrestins. G protein–biased KOR agonists hold promise due to their potential to mitigate side effects such as drug aversion and sedation while preserving analgesic and antipruritic effects. Here, we shed light on the structural
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Actin polymerization counteracts prewetting of N-WASP on supported lipid bilayers bioRxiv. Biophys. Pub Date : 2024-04-15 Tina Wiegand, Jinghui Liu, Anatol W Fritsch, Lutz Vogeley, Isabel Luvalle-Burke, Jan Geisler, Anthony A Hyman, Stephan W Grill
Cortical condensates, transient punctate-like structures rich in actin and the actin nucleation pathway member N-WASP, form during activation of the actin cortex in the C. elegans oocyte. Their emergence and spontaneous dissolution is linked to a phase separation process driven by chemical kinetics. However, the physical process that drives the onset of cortical condensate formation near membranes
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Interior pH Sensing Residue of Human Voltage-Gated Proton Channel Hv1 is Histidine 168 bioRxiv. Biophys. Pub Date : 2024-04-14 Mingzhe Shen, Yandong Huang, Zhitao Cai, Vladimir V. Cherny, Thomas E. DeCoursey, Jana Shen
Themolecular mechanisms governing the human voltage-gated proton channel hHv1 remain elusive.Here we used membrane-enabled hybrid-solvent continuous constant pH molecular dynamics (CpHMD) simulations with pH replica exchange to further evaluate the recently obtained structural models of hHv1 in hyperpolarized (closed channel) and depolarized (open channel) states (Geragotelis, Tobias et al., Proc.
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Overcoming the preferred orientation problem in cryoEM with self-supervised deep-learning bioRxiv. Biophys. Pub Date : 2024-04-14 Yuntao Liu, Hongcheng Fan, Jason Hu, Z. Hong Zhou
While advances in single-particle cryoEM have enabled the structural determination of macromolecular complexes at atomic resolution, particle orientation bias (the so-called "preferred" orientation problem) remains a complication for most specimens. Existing solutions have relied on biochemical and physical strategies applied to the specimen and are often complex and challenging. Here, we develop spIsoNet
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Water Diffusion in the Live Human Brain is Gaussian at the Mesoscale bioRxiv. Biophys. Pub Date : 2024-04-14 Kulam Najmudeen Magdoom, Alexandru V. Avram, Thomas Witzel, Susie Y. Huang, Peter J. Basser
Imaging the live human brain at the mesoscopic scale is a desideratum in basic and clinical neurosciences. Despite the promise of diffusion MRI, the lack of an accurate model relating the measured signal and the associated microstructure has hampered its success. The widely used diffusion tensor MRI (DTI) model assumes an anisotropic Gaussian diffusion process in each voxel, but lacks the ability to
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Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method bioRxiv. Biophys. Pub Date : 2024-04-14 Soumajit Dutta, Diwakar Shukla
New psychoactive substances (NPS) targeting cannabinoid receptor 1 pose a significant threat to society as recreational abusive drugs that have pronounced physiological side effects. These greater adverse effects compared to classical cannabinoids have been linked to the higher downstream β-arrestin signaling. Thus, understanding the mechanism of differential signaling will reveal important structure-activity
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Decoding Proteoforms with Single Acid Resolution Using a Sub-nanometer Diameter Pore bioRxiv. Biophys. Pub Date : 2024-04-14 Apurba Paul, Archith Rayabharam, Punam Murkate, Lisa Almonte, Eveline Rigo, Zhuxin Dong, Ashutosh Kumar, Joshy Joseph, Narayana R. Aluru, Gregory Timp
When a denatured protein isoform (i.e., a proteoform) immersed in electrolyte is impelled by an electric field through a sub-nanometer-diameter pore (i.e., a sub-nanopore) spanning a thin membrane, the sequence of amino acid (AA) residues constituting the proteoform can be directly "read" one at a time by measuring fluctuations in the electrolytic current. Corroborating this assertion, an analysis
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Altered Mechanobiology of PDAC Cells with Acquired Chemoresistance to Gemcitabine and Paclitaxel. bioRxiv. Biophys. Pub Date : 2024-04-13 Alessandro Gregori, Cecilia Bergonzini, Mjriam Capula, Rick Rodrigues de Mercado, Erik H. J. Danen, Elisa Giovannetti, Thomas Schmidt
Background: Pancreatic ductal adenocarcinoma (PDAC) acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding of some biological mechanisms of chemoresistance, much of those mechanisms remain to be uncovered. Mechanobiology, which studies physical properties of cells, holds promise as a potential target for addressing challenges of chemoresistance in PDAC
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Asymmetric Allostery in Estrogen Receptor-α Homodimers Drives Responses to the Ensemble of Estrogens in the Hormonal Milieu bioRxiv. Biophys. Pub Date : 2024-04-13 Charles K Min, Jerome C Nwachukwu, Yingwei Hou, Robin Russo, Alexandra Papa, Jian Min, Rouming Peng, Sung Hoon Kim, Yvonne Zeigler, Erumbi S Rangarajan, Tina Izard, Benita S Katzenellenbogen, John A Katzenellenbogen, Kendall W Nettles
The estrogen receptor-α (ER) is thought to function only as a homodimer, but responds to a variety of environmental, metazoan, and therapeutic estrogens at sub-saturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor
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FLASH Irradiation Regulates IFN-β induction by mtDNA via Cytochrome c Leakage bioRxiv. Biophys. Pub Date : 2024-04-13 Jianfeng Lv, Jianhan Sun, Yunbin Luo, Juntao Liu, Di Wu, Yiyu Fang, Haoyang Lan, Longfei Diao, Yuqi Ma, Yuan Li, Meizhi Wang, Ziming Zhao, Heming Wang, Austin Morris, Wenkang Zhang, Zihao Zhang, Lin Lin, Haoyan Jia, Chao Wang, Tianyi Li, Gerard Mourou, Senlin Huang, Gen Yang, Xueqing Yan
Ultrahigh dose rate radiotherapy (FLASH-RT) is under intensive investigation for its biological benefits. The mechanisms underlying its ability to spare normal tissues while suppress tumor growth still remain controversial. Here we reveal that compared to the low dose rate electron irradiation (0.36 Gy/s), FLASH electron irradiation at 61 or 610 Gy/s enhances the cytochrome c leakage from mitochondria
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RNA complexes with nicks and gaps: thermodynamic and kinetic effects of coaxial stacking and dangling ends bioRxiv. Biophys. Pub Date : 2024-04-13 Marco Todisco, Aleksandar Radakovic, Jack Szostak
Multiple RNA strands can interact in solution and assume a large variety of configurations dictated by their potential for base pairing. Although duplex formation from two complementary oligonucleotides has been studied in detail, we still lack a systematic characterization of the behavior of higher order complexes. Here we focus on the thermodynamic and kinetic effects of an upstream oligonucleotide
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On the critical concentration for net assembly of dynamically unstable polymers bioRxiv. Biophys. Pub Date : 2024-04-13 R. Dyche Mullins
Cytoskeletal and cytomotive filaments are protein polymers that move molecular cargo and organize cellular contents in all domains of life. A key parameter describing the self-assembly of many of these polymers, including actin filaments and microtubules, is the minimum concentration required for polymer formation. This "critical concentration for net assembly" (ccN) is easy to calculate for eukaryotic
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Mechanically Sheared Axially Swept Light-Sheet Microscopy bioRxiv. Biophys. Pub Date : 2024-04-13 Jinlong Lin, Dushyant Mehra, Zach Marin, Xiaoding Wang, Hazel M. Borges, Qionghua Shen, Seweryn Galecki, John Haug, Kevin M. Dean
We present a mechanically sheared image acquisition format for upright and open-top light-sheet microscopes that automatically places data in its proper spatial context. This approach, which reduces computational post-processing and eliminates unnecessary interpolation or duplication of the data, is demonstrated on an upright variant of Axially Swept Light-Sheet Microscopy (ASLM) that achieves a field
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The recombination efficiency of the bacterial integron depends on the mechanical stability of the synaptic complex bioRxiv. Biophys. Pub Date : 2024-04-13 Ekaterina Vorobevskaia, Celine Loot, Didier Mazel, Michael Schlierf
The predominant tool for adaptation in Gram-negative bacteria is a genetic system called integron. Under conditions of stress, it rearranges gene cassettes, ensuring their sampling through expression, to offer a solution for overcoming the initial stress. Integrons are a major actor of multiple antibiotic resistances, a recognized major global health threat. Cassettes are recombined by a unique recombination
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Breaking Down the Bottlebrush: Atomically-Detailed Structural Dynamics of Mucins bioRxiv. Biophys. Pub Date : 2024-04-13 Fiona Kearns, Mia Rosenfeld, Rommie E Amaro
Mucins, the biomolecular components of mucus, are glycoproteins that form a thick physical barrier at all tissue-air interfaces, forming a first line of defense against pathogens. Structural features of mucins and their interactions with other biomolecules remain largely unexplored due to challenges associated with their high-resolution characterization. Combining limited mass spectrometry glycomics
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A Novel Magnetic Field Device: Effects of Magnetic Fields on Planktonic Yeasts and Fungal Mats bioRxiv. Biophys. Pub Date : 2024-04-13 Akila Bandara, Enoki Li, Daniel A Charlebois
Microorganisms evolved within the geomagnetic field and can be affected by magnetic field exposure. However, the mechanisms underlying many magnetic phenomena in microbes remain to be elucidated. We develop a 3D-printed magnetic field exposure device to perform experiments on microbes. This device is designed in AutoCAD, modeled in COMSOL, and validated using a Gaussmeter. Using the magnetic field
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Human Cells for Human Proteins: Isotope Labeling in Mammalian Cells for Functional NMR Studies of Disease-Relevant Proteins bioRxiv. Biophys. Pub Date : 2024-04-13 Philip Rößler, Marco Ruckstuhl, Arnelle Löbbert, Timo Stühlinger, Lucia R. Franchini, Ching-Ju Tsai, Roman Lichtenecker, Binesh Shrestha, Simon H. Rüdisser, Robert Konrat, Gebhard F. X. Schertler, Alvar D. Gossert
In biological and biomedical research the focus progressively moves towards difficult human proteins, which often can only be expressed in higher eukaryotic cells. Nuclear magnetic resonance (NMR) could contribute significantly to the understanding of important proteins as it is one of the most information-rich methods: it allows studying structure, function and dynamics of biomolecules and, importantly
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Molecular architecture of synaptic vesicles. bioRxiv. Biophys. Pub Date : 2024-04-13 Uljana Kravcenko, Max Ruwolt, Jana Kroll, Artsemi Yushkevich, Martina Zenkner, Julia Ruta, Rowaa Lotfy, Erich E Wanker, Christian Rosenmund, Fan Liu, Misha Kudryashev
Synaptic vesicles (SVs) store and transport neurotransmitters to the presynaptic active zone for release by exocytosis. After release, SV proteins and excess membrane are recycled via endocytosis, and new SVs are formed in a clathrin-dependent manner. This process maintains the morphology and complex molecular composition of SVs through multiple recycling rounds. Previous studies explored the molecular
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What can we learn when fitting a simple telegraph model to a complex gene expression model? bioRxiv. Biophys. Pub Date : 2024-04-12 Feng Jiao, Jing Li, Ting Liu, Yifeng Zhu, Wenhao Che, Leonidas Bleris, Chen Jia
In experiments, the distributions of mRNA or protein numbers in single cells are often fitted to the random telegraph model which includes synthesis and decay of mRNA or protein, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by crucial biological mechanisms such as feedback regulation, non-exponential
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Molecular interplay between HURP and Kif18A in mitotic spindle regulation bioRxiv. Biophys. Pub Date : 2024-04-11 Juan M Perez-Bertoldi, Yuanchang Zhao, Akanksha Thawani, Ahmet Yildiz, Eva Nogales
During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imaging in vitro, we demonstrate that Kif18A motility is regulated by HURP. While sparse
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Effect of diffusivity of amyloid beta monomers on the formation of senile plaques bioRxiv. Biophys. Pub Date : 2024-04-11 Andrey V. Kuznetsov
Alzheimer’s disease (AD) presents a perplexing question: why does its development span decades, even though individual amyloid beta (Aβ) deposits (senile plaques) can form rapidly in as little as 24 hours, as recent publications suggest? This study investigates whether the formation of senile plaques can be limited by factors other than polymerization kinetics alone. Instead, their formation may be
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Modulation of α-Synuclein Aggregation Amid Diverse Environmental Perturbation bioRxiv. Biophys. Pub Date : 2024-04-11 Abdul Wasim, Sneha Menon, Jagannath Mondal
Intrinsically disordered protein α-Synuclein (αS) is implicated in Parkinson’s disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process of αS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of αS in aqueous and varied environmental condition
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Valproic Acid Treatment Enhances Chromosome Flexibility and Electron Transport in MCF7 Breast Cancer Cells bioRxiv. Biophys. Pub Date : 2024-04-11 Tanya Agrawal, Debashish Paul, Amita Mishra, Arunkumar Ganesan, Suchetan Pal, Tatini Rakshit
The structural integrity of the chromosomes is essential to every functional process within the eukaryotic nuclei. Chromosomes are DNA-histone complexes essential for the inheritance of genetic information to the offspring and any defect in it is linked to mitotic errors, cancer growth, and cellular aging. Changes in the mechanical properties of a chromosome could lead to its compromised function and
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Alternating Access of a Neurotransmitter:Sodium Symporter Bacterial Homolog Determined from AlphaFold2 Ensembles and DEER Spectroscopy bioRxiv. Biophys. Pub Date : 2024-04-11 Alexandra C. Schwartz, Richard A. Stein, Eva Gil-Iturbe, Matthias Quick, Hassane S. Mchaourab
Neurotransmitter:sodium symporters (NSSs) play critical roles in neural signaling by regulating neurotransmitter uptake into cells powered by sodium electrochemical gradients. Bacterial NSSs orthologs, including MhsT from Bacillus halodurans, have emerged as model systems to understands the structural motifs of alternating access in NSSs and the extent of conservation of these motifs across the family
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Stress granule dysfunction via chromophore-associated light inactivation bioRxiv. Biophys. Pub Date : 2024-04-11 Takumi Koizumi, Ai Fujimoto, Haruka Kawaguchi, Tsumugi Kurosaki, Akira Kitamura
Stress granules (SGs) are cytoplasmic condensates composed of various proteins and RNAs that protect translation-associated machinery from harmful conditions during stress. However, the method of spatio-temporal inactivation of condensates such as SGs in live cells to study cellular phenotypes is still in the process of being demonstrated. Here, we show that the inactivation of SG by chromophore-associated
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Interplay of geometry and mechanics in epithelial wound healing bioRxiv. Biophys. Pub Date : 2024-04-11 Nandhu Krishna Babu, M Sreepadmanabh, Sayantan Dutta, Tapomoy Bhattacharjee
Wound healing is a complex biological process critical for maintaining an organism’s structural integrity and tissue repair following an infection or injury. Recent studies have unveiled the mechanisms involving the coordination of biochemical and mechanical responses in the tissue in wound healing. In this article, we focus on the healing property of an epithelial tissue as a material while the effects
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Assembly of the Bacterial Ribosome with Circularly Permuted rRNA bioRxiv. Biophys. Pub Date : 2024-04-10 Xiyu Dong, Kai Sheng, Luca F.R. Gebert, Sriram Aiyer, Ian J. MacRae, Dmitry Lyumkis, James R. Williamson
Co-transcriptional assembly is an integral feature of the formation of RNA-protein complexes that mediate translation. For ribosome synthesis, prior studies have indicated that the strict order of transcription of rRNA domains may not be obligatory during bacterial ribosome biogenesis, since a series of circularly permuted rRNAs are viable. In this work, we report the insights into assembly of the
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The growth rate of senile plaques is determined by the competition between the rate of deposition of free Aβ aggregates into plaques and the autocatalytic production of free Aβ aggregates bioRxiv. Biophys. Pub Date : 2024-04-10 Andrey V. Kuznetsov
The formation of amyloid beta (Aβ) deposits (senile plaques) is one of the hallmarks of Alzheimer’s disease (AD). This study investigates what processes are primarily responsible for their formation. A model is developed to simulate the diffusion of amyloid beta (Aβ) monomers, the production of free Aβ aggregates through nucleation and autocatalytic processes, and the deposition of these aggregates
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Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure bioRxiv. Biophys. Pub Date : 2024-04-10 Antonio J. Rua, Andrei T. Alexandrescu
Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc-fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711 it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as
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Monolayer force generation and transmission is dictated by focal adhesion distribution bioRxiv. Biophys. Pub Date : 2024-04-10 John Robert Davis, Josephine Solowiej-Wedderburn, Sebastián L. Vega, Jason A. Burdick, Carina Dunlop, Nicolas Tapon
For tissues to develop and maintain their function, cells must orchestrate their behaviour by generating and transmitting contractile forces. These forces are transmitted to their surrounding matrix or neighbouring cells via adhesion complexes. How tissues reach a force-balance is often assumed to involve intercellular stresses counterbalancing those in the substrate. However, experimental findings
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Variational calculus approach to Zernike polynomials with application to fluorescence correlation spectroscopy bioRxiv. Biophys. Pub Date : 2024-04-10 Ivan Gligonov, Jörg Enderlein
Zernike polynomials are a sequence of orthogonal polynomials that play a crucial role in optics and in particular in modeling microscopy systems. First introduced by Frits Zernike in 1934, they are particularly useful in expressing wavefront aberrations and thus imperfections of imaging systems. However, their origin and properties are rarely discussed and proven. Here, we present a novel approach
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Thermodynamic dissipation constrains metabolic versatility of unicellular growth bioRxiv. Biophys. Pub Date : 2024-04-10 Tommaso Cossetto, Jonathan Rodenfels, Pablo Sartori
From deep hydrothermal vents to artificial laboratory conditions, unicellular organisms grow in almost any environment. This is due to metabolic versatility, the capacity of metabolism to extract energy and matter from vastly different chemical substrates. Since growth occurs far from thermodynamic equilibrium, the second law of thermodynamics, which establishes the unavoidability of energy dissipation
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Simulation-based dosimetry of transcranial and intranasal photobiomodulation of the human brain: the roles of wavelength, power density and skin colour bioRxiv. Biophys. Pub Date : 2024-04-10 Hannah Van Lankveld, Anh Q. Mai, Lew Lim, Nazanin Hosseinkhah, Paolo Cassano, J. Jean Chen
Photobiomodulation (PBM) is a novel technique that is actively studied for neuromodulation. However, despite the many in vivo studies, the stimulation protocols for PBM vary amongst studies, and the current understanding of neuromodulation via PBM is limited in terms of the extent of light penetration into the brain and its dosage dependence. Moreover, as near-infrared light can be absorbed by melanin
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Nucleosome wrapping energy in CpG islands and the role of epigenetic base modifications bioRxiv. Biophys. Pub Date : 2024-04-10 Rasa Giniūnaitė, Rahul Sharma, John H. Maddocks, Skirmantas Kriaučionis, Daiva Petkevičiūtė-Gerlach
The majority of vertebrate promoters have a distinct DNA composition, known as a CpG island. Cytosine methylation in promoter CpG islands is associated with a substantial reduction of transcription initiation. We hypothesise that both atypical sequence composition, and epigenetic base modifications may affect the mechanical properties of DNA in CpG islands, influencing the ability of proteins to bind
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Rethinking sinking: Imaging flow fields of natural marine aggregates to infer porosity-dependent changes in sinking velocity and carbon flux bioRxiv. Biophys. Pub Date : 2024-04-10 Clara M. Flintrop, Soeren Ahmerkamp, Nasrollah Moradi, Isabell Klawonn, Jöran März, Cora Hörstmann, Rainer Kiko, Arzhang Khalili, Hans-Peter Grossart, Xosé A. Álvarez-Salgado, Javier Arístegui, Morten H. Iversen
The marine biological carbon pump is mainly driven by the interplay between aggregate sinking velocity and remineralization. Sinking velocity of natural marine aggregates is not routinely measured but often calculated using Stokes’ law, which does not consider size-dependent changes in porosity. We analyzed the flow fields around 81 in situ-formed aggregates using Particle Image Velocimetry (PIV) to
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Exploring new nanopore sensors from the aerolysin family bioRxiv. Biophys. Pub Date : 2024-04-10 Nuria Cirauqui, Juan F. Bada Juarez, Fernando Augusto T. P. Meireles, Julian Barry, Monika Bokori-Brown, Maria J. Marcaida, Chan Cao, Matteo Dal Peraro
Aerolysin-like proteins are a family of β-pore-forming toxins which are widely present in all kingdoms of life. Recently, this family of proteins is gaining attention because of their biotechnological application as nanopore sensors for sensing and sequencing of biomolecules. Here, we explore the possibilities of using the knowledge of the sequence and structure of proteins to screen and explore new
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CryoRhodopsins: a comprehensive characterization of a group of microbial rhodopsins from cold environments bioRxiv. Biophys. Pub Date : 2024-04-10 G.H.U. Lamm, E. Marin, A. Alekseev, A.V. Schellbach, A. Stetsenko, G. Bourenkov, V. Borshchevskiy, M. Asido, M. Agthe, S. Engilberge, S.L. Rose, N. Caramello, A. Royant, T. R. Schneider, A. Bateman, T. Mager, T. Moser, J. Wachtveitl, A. Guskov, K. Kovalev
Microbial rhodopsins are omnipresent on Earth, however the vast majority of them remain uncharacterized. Here we describe a new rhodopsin group from cold-adapted organisms and cold environments, such as glaciers, denoted as CryoRhodopsins (CryoRs). Our data suggest that CryoRs have dual functionality switching between inward transmembrane proton translocation and photosensory activity, both of which
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The Kinetic and Energetic Pull of Chemical Entropy bioRxiv. Biophys. Pub Date : 2024-04-10 Josh E. Baker
Single molecule mechanics studies clearly show that the molecular mechanism of muscle contraction is a force-generating myosin motor switch. However, muscle mechanics and energetics cannot be accounted for by summing up the force-generating chemical steps of independent myosin motors – the energetic contribution of the gradient of myosin motors across the force-generating chemical step is required