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Effect Of Two Activators On The Gating Of A K2P Channel bioRxiv. Biophys. Pub Date : 2024-04-24 Edward Mendez-Otalvaro, Wojciech Kopec, Bert L. de Groot
TREK1, a two-pore-domain (2P) mammalian potassium (K+) channel, regulates the resting potential across cell membranes, presenting a promising therapeutic target for neuropathy treatment. The gating of this channel converges in the conformation of the narrowest part of the pore: the selectivity filter (SF). Various hypotheses explain TREK1 gating modulation, including the dynamics of loops connecting
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Mechanical characterization of regenerating Hydra tissue spheres bioRxiv. Biophys. Pub Date : 2024-04-24 Thomas Perros, Anais Biquet-Bisquert, Zacchari Ben Meriem, Morgan Delarue, Pierre Joseph, Philippe Marcq, Olivier Cochet-Escartin
Hydra vulgaris, long known for its remarkable regenerative capabilities, is also a longstanding source of inspiration for models of spontaneous patterning. Recently, it became clear that early patterning during Hydra regeneration is an integrated mechano-chemical process where morphogen dynamics is influenced by tissue mechanics. One roadblock to understand Hydra self-organization is our lack of knowledge
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Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states bioRxiv. Biophys. Pub Date : 2024-04-24 Brian MacTavish, Di Zhu, Jinsai Shang, Qianzhen Shao, Zhongyue Yang, Theodore Kamenecka, Douglas Kojetin
Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists—a limitation that restricts understanding of the functional NR conformational
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Nap1 and Kap114 co-chaperone H2A-H2B and facilitate targeted histone release in the nucleus bioRxiv. Biophys. Pub Date : 2024-04-23 Ho Yee Joyce Fung, Ashley B Neisman, Natalia E Bernardes, Jenny Jiou, Yuh Min Chook
Core histones are synthesized and processed in the cytoplasm before transport into the nucleus for assembly into nucleosomes; however, they must also be chaperoned as free histones are toxic. The importin Kap114 binds and transports histone H2A-H2B into the yeast nucleus, where RanGTP facilitates H2A-H2B release. Kap114 and H2A-H2B also bind the Nap1 histone chaperone, which is found in both the cytoplasm
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Passage of the HIV capsid cracks the nuclear pore bioRxiv. Biophys. Pub Date : 2024-04-23 Jan Philipp Kreysing, Maziar Heidari, Vojtech Zila, Sergio Cruz-Leon, Agnieszka Obarska-Kosinska, Vibor Laketa, Sonja Welsch, Juergen Koefinger, Beata Turonova, Gerhard Hummer, Hans-Georg Kraeusslich, Martin Beck
Upon infection, human immunodeficiency virus (HIV-1) releases its cone-shaped capsid into the cytoplasm of infected T-cells and macrophages. As its largest known cargo, the capsid enters the nuclear pore complex (NPC), driven by interactions with numerous FG-repeat nucleoporins (FG-Nups). Whether NPCs structurally adapt to capsid passage and whether capsids are modified during passage remains unknown
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PUFA stabilizes a conductive state of the selectivity filter in IKs channels bioRxiv. Biophys. Pub Date : 2024-04-23 Alessia Golluscio, Jodene Eldstrom, Jessica J Jowais, Marta Elena Perez, Kevin Peter Cunningham, Alicia De La Cruz, Xiaoan Wu, David Fedida, Peter Larsson, D. Peter Tieleman, Valentina Corradi
The KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause Long QT Syndrome. A therapeutical intervention for this syndrome is based on targeting IKs channels to restore channel function. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and cause a shift
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Internal unwinding mechanism of a replicative helicase bioRxiv. Biophys. Pub Date : 2024-04-23 Taha Shahid, Muhammad Tehseen, Lubna Alhudhali, Alice R Clark, Christos G Savva, Samir M Hamdan, Alfredo De Biasio
Ring-shaped hexameric helicases are nucleotide hydrolases that unwind double-stranded DNA into single strands, a necessary step in DNA replication. Critical to understanding their function are two outstanding questions: the location of DNA strand separation within the helicase, particularly at the onset of unwinding, and the precise dynamic linkage between nucleotide hydrolysis and DNA translocation
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Potassium-mediated bacterial chemotactic response bioRxiv. Biophys. Pub Date : 2024-04-23 Chi Zhang, Rongjing Zhang, Junhua Yuan
Bacteria in biofilms secrete potassium ions to attract free swimming cells. However, the basis of chemotaxis to potassium remains poorly understood. Here, using a microfluidic device, we found that Escherichia coli can rapidly accumulate in regions of high potassium concentration on the order of millimoles. Using a bead assay, we measured the dynamic response of individual flagellar motors to stepwise
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The mechanism of mammalian proton-coupled peptide transporters bioRxiv. Biophys. Pub Date : 2024-04-22 Simon M Lichtinger, Joanne L Parker, Simon Newstead, Philip Biggin
Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold
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Regulation of Chromatin Modifications through Coordination of Nucleus Size and Epithelial Cell Morphology Heterogeneity bioRxiv. Biophys. Pub Date : 2024-04-22 Alexandra Bermudez, Zoe Latham, Alex Ma, Dapeng Bi, Jimmy Hu, Neil Lin
Cell morphology heterogeneity within epithelial collectives is a pervasive phenomenon intertwined with tissue mechanical properties. Despite its widespread occurrence, the underlying mechanisms driving cell morphology heterogeneity and its consequential biological ramifications remain elusive. Here, we investigate the dynamic evolution of epithelial cell morphology and nucleus morphology during crowding
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Coupling the role of lipids to the conformational dynamics of the ABC transporter P-gp bioRxiv. Biophys. Pub Date : 2024-04-22 Dario De Vecchis, Lars Schäfer
The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) is a multidrug efflux pump that is overexpressed in a variety of cancers and associated with the drug resistance phenomenon. P-gp structures were previously determined in detergent and in nanodiscs, in which different transmembrane helix conformations were found, "straight" and "kinked", respectively, indicating a possible role of the
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Morphogenesis of bacterial colonies in polymeric environments bioRxiv. Biophys. Pub Date : 2024-04-22 Sebastian Gonzalez La Corte, Corey A Stevens, Gerardo Cárcamo-Oyarce, Katharina Ribbeck, Ned S Wingreen, Sujit S Datta
Many bacteria live in polymeric fluids, such as mucus, environmental polysaccharides, and extracellular polymers in biofilms. However, lab studies typically focus on cells in polymer-free fluids. Here, we show that interactions with polymers shape a fundamental feature of bacterial life---how they proliferate in space in multicellular colonies. Using experiments, we find that when polymer is sufficiently
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A Bayesian Solution to Count the Number of Molecules within a Diffraction Limited Spot bioRxiv. Biophys. Pub Date : 2024-04-22 Alexander Hillsley, Johannes Stein, Paul W Tillberg, David L Stern, Jan Funke
We address the problem of inferring the number of independently blinking fluorescent light emitters, when only their combined intensity contributions can be observed at each timepoint. This problem occurs regularly in light microscopy of objects that are smaller than the diffraction limit, where one wishes to count the number of fluorescently labelled subunits. Our proposed solution directly models
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X-ray Crystallographic and Hydrogen Deuterium Exchange Studies Confirm Alternate Kinetic Models for Homolog Insulin Monomers bioRxiv. Biophys. Pub Date : 2024-04-22 Esra Ayan, Miray Turk, Ozge Tatli, Elek Telek, Baran Dingiloglu, Gizem Dinler Doganay, Hasan Demirci
Despite the crucial role of various insulin analogs in achieving satisfactory glycemic control, a comprehensive understanding of their dynamic mechanisms still holds the potential to further optimize ultra-fast-acting insulin analogs, thus significantly improving the well-being of individuals with Type 1 Diabetes. Here, we present new insights derived from our 2.5 Å resolution X-ray crystal structure
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Using muscle-tendon load limits to assess unphysiological musculoskeletal model deformation and Hill-type muscle parameter choice bioRxiv. Biophys. Pub Date : 2024-04-22 Lennart V. Nölle, Isabell Wochner, Maria Hammer, Syn Schmitt
Musculoskeletal simulations are a useful tool for improving our understanding of the human body. However, the physiological validity of predicted kinematics and forces is highly dependent upon the correct calibration of muscle parameters and the structural integrity of a model’s internal skeletal structure. In this study, we show how ill-tuned muscle parameters and unphysiological deformations of a
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Detecting directed motion and confinement in single-particle trajectories using hidden variables bioRxiv. Biophys. Pub Date : 2024-04-21 Francois Simon, Guillaume Ramadier, Ines Fonquernie, Janka Zsok, Sergiy Patskovsky, Michel Meunier, Caroline Boudoux, Elisa Dultz, Lucien E. Weiss
Single-particle tracking is a powerful tool for understanding protein dynamics and characterizing microenvironments. As the motion of unconstrained nanoscale particles is governed by Brownian diffusion, deviations from this behavior are biophysically insightful. The stochastic nature of particle movement and the presence of localization error, however, pose a challenge for robust classification of
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Site-Specific Investigation of DNA Holliday Junction Dynamics and Structure with 6-Methylisoxanthopterin, a Fluorescent Guanine Analog bioRxiv. Biophys. Pub Date : 2024-04-21 Zane Lombardo, Ishita Mukerji
DNA Holliday Junction (HJ) formation and resolution is requisite for maintaining genomic stability in processes such as replication fork reversal and double-strand break repair. If HJs are not resolved, chromosome disjunction and aneuploidy result, hallmarks of tumor cells. To understand the structural features that lead to processing of these four-stranded joint molecule structures, we seek to identify
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The advantage of periodic over constant signalling in microRNA-mediated repression bioRxiv. Biophys. Pub Date : 2024-04-21 Elsi Ferro, Candela Lucia Szischik, Alejandra C Ventura, Carla Bosia
Cells have been found out to exploit oscillatory rather than constant gene expression to encode biological information. Temporal features of oscillations such as pulse frequency and amplitude have been shown determinant for the outcome of signaling pathways. However, little effort has been devoted to unveiling the role of pulsatility in the context of post-transcriptional gene regulation, where microRNAs
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Image-based Strain Analysis Reveals Intracellular Strain Controlled by Nucleo-Cytoskeletal Coupling bioRxiv. Biophys. Pub Date : 2024-04-21 Jerry Chen, Iris Sloan, Alexandra Bermudez, David Choi, Ming-Heng Tsai, Lihua Jin, Jimmy Hu, Neil Lin
Cells can sense and transduce mechanical forces, such as stretching, and convert these signals into diverse cell biological events. While much effort has been devoted to identifying the downstream biochemical and cellular responses, it is equally crucial to pinpoint the mechanical stimuli within a cell driving these responses. Specifically, much remains unknown about how intracellular strains are distributed
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Exploring the Influence of Pore Shape on Conductance and Permeation bioRxiv. Biophys. Pub Date : 2024-04-21 David Seiferth, Philip C Biggin
There are increasing numbers of ion channel structures featuring heteromeric subunit assembly, exemplified by synaptic α1βB Glycine and α4β2 Nicotinic receptors. These structures exhibit inherent pore asymmetry, but the relevance of this to function is unknown. Furthermore, molecular dynamics simulations performed on symmetrical homomeric channels often leads to thermal distortion whereby conformations
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Heterogeneous distribution of kinesin-streptavidin complexes revealed by Mass Photometry bioRxiv. Biophys. Pub Date : 2024-04-21 Jing Xu, Nathaniel Brown, Yeonee Seol, Keir C. Neuman
Kinesin-streptavidin complexes are widely used in microtubule-based active-matter studies. The stoichiometry of the complexes is empirically tuned but experimentally challenging to determine. Here, mass photometry measurements reveal heterogenous distributions of kinesin-streptavidin complexes. Our binding model indicates that heterogeneity arises from both the kinesin-streptavidin mixing ratio and
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Intramolecular Communication and Allosteric Sites in Enzymes Unraveled by Time-Dependent Linear Response Theory bioRxiv. Biophys. Pub Date : 2024-04-20 Bang-Chieh Huang, Yi-Yun Cheng, Chi-Hong Chang-Chein, Chao-Ling Yao, Lee-Wei Yang
It has been an established idea in recent years that protein is a physiochemically connected network. Allostery, understood in this new context, is a manifestation of residue communicating between remote sites in this network, and hence a rising interest to identify functionally relevant communication pathways and the frequent communicators within. However, there have been limited computationally trackable
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Lipid-dependent conformational dynamics of bacterial ATP-binding cassette transporter Sav1866 bioRxiv. Biophys. Pub Date : 2024-04-20 Shadi A Asadian, Jeevapani Hettige, Mahmoud Moradi
Sav1866, a bacterial ATP-binding cassette (ABC) exporter, plays a crucial role in cellular processes by facilitating the efflux of a diverse range of substrates, including drugs, chemotherapeutic agents, peptides, and lipids. This efflux activity significantly impacts the effectiveness of various therapies against bacterial infections. In our recent investigation, we focused on understanding the conformational
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Cholesterol Dependence on the Conformational Changes of Metabotropic Glutamate Receptor 1 bioRxiv. Biophys. Pub Date : 2024-04-20 Ugochi H Isu, Shadi A Badiee, Adithya Polasa, Seyed Hamid Tabari, Mortaza Derakhshani-Molayousefi, Mahmoud Moradi
Metabotropic glutamate receptors (mGluRs) are class C G protein-coupled receptors that function as obligate dimers in regulating neurotransmission and synaptic plasticity in the central nervous system. The mGluR1 subtype has been shown to be modulated by the membrane lipid environment, particularly cholesterol, though the molecular mechanisms remain elusive. In this study, we employed all-atom molecular
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Nuclear size-regulated emergence of topological packing order on growing human lung alveolospheres bioRxiv. Biophys. Pub Date : 2024-04-20 Wenhui Tang, Jessie Huang, Adrian F. Pegoraro, James H. Zhang, Yiwen Tang, Dapeng Bi, Darrell N. Kotton, Ming Guo
Within multicellular living systems, cells coordinate their positions with spatiotemporal accuracy to form various structures, setting the clock to control developmental processes and trigger maturation. These arrangements can be regulated by tissue topology, biochemical cues, as well as mechanical perturbations. However, the fundamental rules of how local cell packing order is regulated in forming
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Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1 Revealed by Microsecond-Level Molecular Dynamics Simulation bioRxiv. Biophys. Pub Date : 2024-04-20 Ugochi H Isu, Adithya Polasa, Mahmoud Moradi
The cannabinoid receptor CB1 is a G protein-coupled receptor that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics simulations, we identified
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Dynamic Formation of the Protein-Lipid Pre-fusion State bioRxiv. Biophys. Pub Date : 2024-04-20 Maria Bykhovskaia
Synaptic vesicles (SVs) release neuronal transmitters by the fusion with the presynaptic membrane (PM), and the SV protein Synaptotagmin 1 (Syt1) serves as a calcium sensor for evoked fusion. Syt1 is thought to trigger fusion by penetrating into PM upon calcium binding, however the mechanistic detail of this process are still debated. Syt1 interacts with the SNARE complex, a coiled-coil four-helical
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Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress bioRxiv. Biophys. Pub Date : 2024-04-20 Adrian M. Wong, Itay Budin
Cell organelles feature characteristic lipid compositions that lead to differences in membrane properties. In living cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to membrane packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells, so it is challenging to characterize membrane properties
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Calculating Protein-Ligand Residence Times Through State Predictive Information Bottleneck based Enhanced Sampling bioRxiv. Biophys. Pub Date : 2024-04-20 Suemin Lee, Dedi Wang, Markus Seeliger, Pratyush Tiwary
Understanding drug residence times in target proteins is key to improving drug efficacy and understanding target recognition in biochemistry. While drug residence time is just as important as binding affinity, atomic-level understanding of drug residence times through molecular dynamics (MD) simulations has been difficult primarily due to the extremely long timescales. Recent advances in rare event
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Tandem-repeat proteins introduce tuneable properties to engineered biomolecular condensates bioRxiv. Biophys. Pub Date : 2024-04-20 Tin Long Chris Ng, Mateo P. Hoare, M. Julia Maristany, Ellis J. Wilde, Tomas Sneideris, Jan Huertas, Belinda K. Agbetiameh, Mona Furukawa, Jerelle A. Joseph, Tuomas P.J. Knowles, Rosana Collepardo-Guevara, Laura S. Itzhaki, Janet R. Kumita
The ability of the cell to rapidly partition biomolecules into biomolecular condensates has been linked to a diverse range of cellular functions. To understand how the structural and dynamic attributes of these biomolecular condensates are linked with their biological roles, it is important to develop synthetic systems that allow systematic tuning of their physicochemical properties. Here, we describe
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High-Throughput DNA melt measurements enable improved models of DNA folding thermodynamics bioRxiv. Biophys. Pub Date : 2024-04-20 Yuxi Ke, Eesha Sharma, Hannah K. Wayment-Steele, Winston R. Becker, Anthony Ho, Emil Marklund, William J. Greenleaf
DNA folding thermodynamics are central to many biological processes and biotechnological applications involving base-pairing. Current methods for predicting stability from DNA sequence use nearest-neighbor (NN) models that struggle to accurately capture the diverse sequence-dependency of elements other than Watson-Crick base pairs, likely due to insufficient experimental data. We introduce a massively
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Aggregation of an FG nucleoporin under crowded conditions bioRxiv. Biophys. Pub Date : 2024-04-19 Laura Maguire, Sophie Reskin, Kathryn P Wall, Elena Arroyo, Paul Marchando, A. M. Whited, Annette Erbse, Steven T Whitten, Loren E Hough
Macromolecular crowding can affect the aggregation behavior of intrinsically disordered proteins in unexpected ways. We studied the aggregation of a peptide derived from the disordered FG nucleoporins which line the nuclear pore complex. We measured its aggregation kinetics in the presence of both inert and non-specifically interacting crowding agents. Using fluorescence emission and NMR spectroscopy
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Swimming kinematics of rainbow trout behind cylinder arrays: the effect of vortex street periodicity and turbulence kinetic energy bioRxiv. Biophys. Pub Date : 2024-04-19 David Sparks, Edwin Rajeev, Alberto Canestrelli, James C. Liao
Fish in the wild often contend with complex flows that are produced by natural and artificial structures. Research into fish interactions with turbulence often investigates metrics such as turbulence kinetic energy (TKE) or fish positional location, with less attention paid to the specific interactions between vortex organization and body swimming kinematics. Here we compare the swimming kinematics
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Elucidating Electronic Structure Variations in Nucleic Acid-Protein Complexes Involved in Transcription Regulation Using a Tight-Binding Approach bioRxiv. Biophys. Pub Date : 2024-04-19 Likai Du, Chengbu Liu
Transcription factor (TF) are proteins that regulates the transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. Nucleic acid-protein interactions are crucial in regulating transcription in biological systems. This work presents a quick and convenient method for constructing tight-binding models and offers physical insights into the electronic structure
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Dynamic binding of the bacterial chaperone Trigger factor to translating ribosomes bioRxiv. Biophys. Pub Date : 2024-04-19 Tora Havermark, Mikhail Metelev, Erik Lundin, Ivan L Volkov, Magnus Johansson
The bacterial chaperone Trigger factor (TF) binds to ribosome-nascent chain complexes (RNCs) and co-translationally aids the folding of proteins in bacteria. Decades of studies have given a broad, but often conflicting, description of the substrate specificity of TF, its RNC-binding dynamics, and competition with other RNC-binding factors, such as the Signal Recognition Particle (SRP). Previous RNC-binding
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Deciphering the Inter-domain Decoupling in the Gram-negative Bacterial Membrane Insertase bioRxiv. Biophys. Pub Date : 2024-04-19 Adithya Polasa, Shadi A Badiee, Mahmoud Moradi
YidC is a membrane protein that plays an important role in inserting newly generated proteins into lipid membranes. The Sec-dependent complex is responsible for inserting proteins into the lipid bilayer, and this process is facilitated by YidC in bacteria. In addition, YidC acts as a chaperone during the folding process of proteins. Multiple investigations have conclusively shown that the gram-positive
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Mechanistic Insights into ASO-RNA Complexation: Advancing Antisense Oligonucleotide Design Strategies. bioRxiv. Biophys. Pub Date : 2024-04-18 Johanna Horberg, Antonio Carlesso, Anna Reymer
Oligonucleotide drugs, an emerging modulator class, hold promise for targeting previously undruggable biomacromolecules. To date, only 18 oligonucleotide drugs, including sought-after antisense oligonucleotides (ASO) and splice-switching oligonucleotides (SSO), have FDA approval. These agents effectively bind mRNA, inducing degradation or modulating splicing. Current oligonucleotide drug design strategies
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Break-up and Recovery of Harmony between Direct and Indirect Pathways in The Basal Ganglia; Huntington's Disease and Treatment bioRxiv. Biophys. Pub Date : 2024-04-18 Sang-Yoon Kim, Woochang Lim
The basal ganglia (BG) in the brain exhibit diverse functions for motor, cognition, and emotion. Such BG functions could be made via competitive harmony between the two competing pathways, direct pathway (DP) (facilitating movement) and indirect pathway (IP) (suppressing movement). As a result of break-up of harmony between DP and IP, there appear pathological states with disorder for movement, cognition
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Bond strength between receptor binding domain of spike protein and human angiotensin converting enzyme-2 using machine learning. bioRxiv. Biophys. Pub Date : 2024-04-18 Abdulmateen Adebiyi, Puja Adhikari, Praveen Rao, Wai-Yim Ching
The spike protein (S-protein) of SARS-CoV-2 plays an important role in binding, fusion, and host entry. In this study, we have predicted interatomic bond strength between receptor binding domain (RBD) and angiotensin converting enzyme-2 (ACE2) using machine learning (ML), that matches with expensive ab initio calculation result. We collected bond order result from ab initio calculations. We selected
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Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation bioRxiv. Biophys. Pub Date : 2024-04-18 Qin Ni, Zhuoxu Ge, Yizeng Li, Gabriel Shatkin, Jinyu Fu, Kaustav Bera, Yuhang Yang, Yichen Wang, Anindya Sen, Yufei Wu, Ana C.N. Vasconcelosi, Andrew P. Feinberg, Konstantinos Konstantopoulos, Sean X. Sun
Mammalian cells can rapidly respond to osmotic and hydrostatic pressure imbalances during an environmental change, generating large fluxes of water and ions that alter cell volume within minutes. While the role of ion pump and leak in cell volume regulation has been well-established, the potential contribution of the actomyosin cytoskeleton and its interplay with ion transporters is unclear. We discovered
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Axial de-scanning using remote focusing in the detection arm of light-sheet microscopy bioRxiv. Biophys. Pub Date : 2024-04-18 Hassan Dibaji, Ali Kazemi Nasaban Shotorban, Rachel M Grattan, Shayna Lucero, David J Schodt, Keith A Lidke, Jonathan Petruccelli, Diane S Lidke, Sheng Liu, Tonmoy Chakraborty
The ability to image at high speeds is necessary in biological imaging to capture fast-moving or transient events or to efficiently image large samples. However, due to the lack of rigidity of biological specimens, carrying out fast, high-resolution volumetric imaging without moving and agitating the sample has been a challenging problem. Pupil-matched remote focusing has been promising for high NA
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Discovering cryptic pocket opening and binding of a stimulant derivative in a vestibular site of the 5-HT3A receptor bioRxiv. Biophys. Pub Date : 2024-04-18 Nandan Haloi, Emelia Karlsson, Rebecca J. Howard, Erik Lindahl
Ligand-gated ion channels propagate electrochemical signals in the nervous system. A diverse set of allosteric modulators including stimulants, anesthetics, and lipids regulate their function; however, structures of ligand-bound complexes can be difficult to capture by experimental methods, particularly when binding is dynamic or transient. Here, we used computational methods and electrophysiology
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Viscoelasticity of globular protein-based biomolecular condensates bioRxiv. Biophys. Pub Date : 2024-04-18 Rachel S Fisher, Allie C Obermeyer
The phase separation of biomolecules into biomolecular condensates has emerged as a ubiquitous cellular process. Understanding how intrinsically disordered protein sequence controls condensate formation and material properties has provided fundamental biological insights and led to the development of functional synthetic condensates. While these studies provide a valuable framework to understand subcellular
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Constant-pH molecular dynamics simulations of closed and open states of a proton-gated ion channel bioRxiv. Biophys. Pub Date : 2024-04-18 Anton Jansen, Paul Bauer, Rebecca J Howard, Berk Hess, Erik Lindahl
Although traditional molecular dynamics simulations successfully capture a variety of different molecular interactions, the protonation states of titratable residues are kept static. A recent constant-pH molecular dynamics implementation in the GROMACS package allows pH effects to be captured dynamically, and promises to provide both the accuracy and computational performance required for studying
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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