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  • Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs
    bioRxiv. Biophys. Pub Date : 2020-05-28
    Zhe Li; Xin Li; Yi-You Huang; Yaoxing Wu; Lingli Zhou; Runduo Liu; Deyan Wu; Lei Zhang; Hao Liu; Ximing Xu; Yuxia Zhang; Jun Cui; Chang-Guo Zhan; Xin Wang; Hai-Bin Luo

    Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and, thus, repurpose them for treatment of COVID-19. In general, a drug

    更新日期:2020-05-28
  • Direct digital sensing of proteins in solution through single-molecule optofluidics
    bioRxiv. Biophys. Pub Date : 2020-05-28
    Georg Krainer; Kadi L. Saar; William E. Arter; Raphaël P.B. Jacquat; Quentin Peter; Pavankumar Challa; Christopher G. Taylor; David Klenerman; Tuomas P.J. Knowles

    Highly sensitive detection of proteins is of central importance to biomolecular analysis and diagnostics. Conventional protein sensing assays, such as ELISAs, remain reliant on surface-immobilization of target molecules and multi-step washing protocols for the removal of unbound affinity reagents. These features constrain parameter space in assay design, resulting in fundamental limitations due to

    更新日期:2020-05-28
  • Diffusion assessment through image processing: beyond the point-source paradigm
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Eugeny B. Postnikov; Anton A. Namykin; Oxana V. Semyachkina-Glushkovskaya; Dmitry E. Postnov

    The quantification of transport processes of different substances in the brain's parenchyma is important in the context of understanding brain functioning. Most of the currently used methods for assessment of the effective diffusion coefficient rely on the point-source paradigm. We propose a method for the quantitative characterization of the diffusion process in the brain's parenchyma using a set

    更新日期:2020-05-27
  • Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Alice Douangamath; Daren Fearon; Paul Gehrtz; Tobias Krojer; Petra Lukacik; C. David Owen; Efrat Resnick; Claire Strain-Damerell; Anthony aimon; Péter Ábrányi-Balogh; Jose Brandaõ-Neto; Anna Carberry; Gemma Davison; Alexandre Dias; Thomas D Downes; Louise Dunnett; Michael Fairhead; James D Firth; S. Paul Jones; Aaron Keely; György M Keserü; Hanna F Klein; Matthew P Martin; Martin E.M. Noble; Peter

    COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach

    更新日期:2020-05-27
  • Collective protection and transport in entangled biological and robotic active matter
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Yasemin Ozkan Aydin; Daniel I Goldman; M. Saad Bhamla

    Living systems at all scales aggregate in large numbers for a variety of functions including mating, predation, and survival. The majority of such systems consist of unconnected individuals that collectively flock, school or swarm. However some aggregations involve physically entangled individuals, which can confer emergent mechanofunctional material properties to the collective. Here we study in laboratory

    更新日期:2020-05-27
  • Combined Selective Plane Illumination Microscopy and FRAP maps intranuclear diffusion of NLS-GFP
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Chad M Hobson; E. Timothy O'Brien; Michael R. Falvo; Richard Superfine

    Since its initial development in 1976, fluorescence recovery after photobleaching (FRAP) has been one of the most popular tools for studying diffusion and protein dynamics in living cells. Its popularity is derived from the widespread availability of confocal microscopes and the relative ease of the experiment and analysis. FRAP, however, is limited in its ability to resolve spatial heterogeneity.

    更新日期:2020-05-27
  • Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Cecilia Hognon; Tom Miclot; Cristina Garcia Iriepa; Antonio France-Monerris; Stephanie Grandemange; Alessio Terenzi; Marco Marazzi; Giampaolo Barone; Antonio Monari

    Coronaviruses may produce severe acute respiratory syndrome (SARS). Indeed, a new SARS-type virus, SARS-CoV-2, is responsible of a global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by using all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and

    更新日期:2020-05-27
  • DNA Binding Induces a cis to trans Switch in Cre Recombinase to Enable Intasome Assembly
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Aparna Unnikrishnan; Carlos D Amero; Deepak Kumar Yadav; Kye Stachowski; Devante Potter; Mark Foster

    Mechanistic understanding of DNA recombination in the Cre-loxP system has largely been guided by crystallographic structures of tetrameric synaptic complexes. Those studies have suggested a role for protein conformational dynamics that has not been well characterized at the atomic level. We used solution NMR to discover the link between intrinsic flexibility and enzyme function in Cre recombinase.

    更新日期:2020-05-27
  • Molecular interaction mechanism of 14-3-3ε protein with phosphorylated Myeloid leukemia factor 1 revealed by an enhanced conformational sampling
    bioRxiv. Biophys. Pub Date : 2020-05-27
    Junichi Higo; Takeshi Kawabata; Ayumi Kusaka; Kota Kasahara; Narutoshi Kamiya; Ikuo Fukuda; Kentaro Mori; Yutaka Hata; Yoshifumi Fukunishi; Haruki Nakamura

    An enhanced conformational sampling, a genetic-algorithm-based multidimensional virtual-system coupled molecular dynamics (GA-based mD-VcMD), was applied to a peptide, phosphorylated Myeloid leukemia factor 1 (pMLF1), binding to a receptor protein, 14-3-3ε, in an explicit solvent. This method provides an equilibrated ensemble at room temperature, from which a density map of pMLF1 around 14-3-3ε can

    更新日期:2020-05-27
  • Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Ryan R. Cheng; Vinicius Contessoto; Erez Lieberman Aiden; Peter G Wolynes; Michele Di Pierro; José Nelson Onuchic

    We study the structural ensembles of human chromosomes across different cell types. Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through super-resolution microscopy. We demonstrate using a combination of machine learning and polymer physics simulations that epigenetic information can be used to predict

    更新日期:2020-05-26
  • Robustification of RosettaAntibody and Rosetta SnugDock
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Jeliazko R Jeliazkov; Rahel Frick; Jing Zhou; Jeffrey J Gray

    In recent years, the observed antibody sequence space has grown exponentially due to advances in high-throughput sequencing of immune receptors. The rise in sequences has not been mirrored by a rise in structures, as experimental structure determination techniques have remained low-throughput. Computational modeling, however, has the potential to close the sequence–structure gap. To achieve this goal

    更新日期:2020-05-26
  • Electric field induced wetting of a hydrophobic gate in a model nanopore based on the 5-HT3 receptor channel
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Gianni Klesse; Stephen J Tucker; Mark Sansom

    In this study we examined the influence of a transmembrane voltage on the hydrophobic gating of nanopores using molecular dynamics simulations. We observed electric field induced wetting of a hydrophobic gate in a biologically inspired model nanopore based on the 5-HT3 receptor in its closed state, with a field of at least ∼100 mV nm−1 was required to hydrate the pore. We also found an unequal distribution

    更新日期:2020-05-26
  • Intercalative DNA binding governs fluorescence enhancement of SYBR Gold
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Pauline J. Kolbeck; Willem Vanderlinden; Thomas Nicolaus; Christian Gebhardt; Thorben Cordes; Jan Lipfert

    SYBR Gold is a commonly used and particularly bright fluorescent DNA stain, however, its binding mode to DNA remains controversial. Here, we quantitate SYBR Gold binding to DNA using two complementary approaches. We use mechanical micromanipulation with magnetic tweezers (MT) to determine the effects of SYBR Gold binding on DNA length, twist, and mechanical properties. The MT assay reveals systematic

    更新日期:2020-05-26
  • Structural Insights on Fusion Mechanisms of Extracellular Vesicles with Model Plasma Membrane
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Fabio Perissinotto; Valeria Maria Rondelli; Beatrice Senigagliesi; Paola Brocca; Laszlo Almasy; Laszlo Bottyan; Daniel Geza Merkel; Barbara Sartori; Heinz Amenitsch; Karin Pachler; Magdalena Mayr; Mario Gimona; Eva Rohde; Loredana Casalis; Pietro Parisse

    Extracellular vesicles (EVs) represent a potent intercellular communication system. Within a lipid bilayer such small vesicles transport biomolecules between cells and throughout the body, strongly influencing the fate of recipient cells. Due to their specific biological functions they have been proposed as biomarkers for various diseases and as optimal candidates for therapeutic applications. Despite

    更新日期:2020-05-26
  • Distinct domain requirements for EAP45 in HIV budding, late endosomal recruitment, and cytokinesis
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Bo Meng; Pedro P Vallejo Ramirez; Katharina M Scherer; Ezra Bruggeman; Julia C Kenyon; Clemens F Kaminski; Andrew M Lever

    The scission of lipid membranes is a common biological process, often mediated by ESCRT complexes in concert with VPS4 assembling around the separation point. The functions of the ESCRT-I and ESCRT-III complexes are well established in certain of these cellular processes; however, the role of ESCRT- II remains contentious. Here, we devised a SNAP-tag fluorescent labelling strategy to understand the

    更新日期:2020-05-26
  • ATP-driven non-equilibrium activation of kinase clients by the molecular chaperone Hsp90
    bioRxiv. Biophys. Pub Date : 2020-05-26
    Huafeng Xu

    The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this cycle enables

    更新日期:2020-05-26
  • Glutamate transporters contain a conserved chloride channel with two hydrophobic gates
    bioRxiv. Biophys. Pub Date : 2020-05-25
    Ichia Chen; Shashank Pant; Qianyi Wu; Rosemary Cater; Meghna Sobti; Robert Vandenberg; Alastair G Stewart; Emad Tajkhorshid; Josep Font; Renae M Ryan

    Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, therefore its precise control is vital for maintaining normal brain function and preventing excitotoxicity1. Removal of extracellular glutamate is achieved by plasma membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism2-5. Glutamate transporters

    更新日期:2020-05-25
  • Endocytosis against high turgor pressure is made easier by partial protein coating and a freely rotating base
    bioRxiv. Biophys. Pub Date : 2020-05-25
    Rui Ma; Julien Berro

    During clathrin-mediated endocytosis, a patch of flat plasma membrane is deformed into a vesicle. In walled cells, such as plants and fungi, the turgor pressure is high and pushes the membrane against the cell wall, thus hindering membrane internalization. In this paper, we study how a patch of membrane is deformed against turgor pressure by force and by curvature-generating proteins. We show that

    更新日期:2020-05-25
  • Conformational maps of human 20S proteasomes reveal PA28- and immuno-dependant inter-ring crosstalks
    bioRxiv. Biophys. Pub Date : 2020-05-25
    Jean Lesne; Marie Locard-Paulet; Julien Parra; Dusan Zivkovic; Marie-Pierre Bousquet; Odile Burlet-Schiltz; Julien Marcoux

    Here, we used for the first time Hydrogen-Deuterium eXchange coupled to Mass Spectrometry (HDX-MS) to investigate conformational differences between the human standard 20S (std20S) and immuno 20S (i20s) proteasomes alone or in complex with PA28αβ or PA28γ activators. Their solvent accessibility was analyzed through a dedicated bioinformatic pipeline including stringent statistical analysis and 3D visualization

    更新日期:2020-05-25
  • Structural visualization of septum formation in Staphylococcus warneri using atomic force microscopy
    bioRxiv. Biophys. Pub Date : 2020-05-24
    Hai-Nan Su; Kang Li; Xiao-Xue Yuan; Meng-Yao Zhang; Si-Min Liu; Xiu-Lan Chen; Lu-Ning Liu; Yu-Zhong Zhang

    Cell division of Staphylococcus adopts a 'popping' mechanism that mediates extremely rapid separation of the septum. Elucidating the structure of the septum is crucial for understanding this exceptional bacterial cell division mechanism. Here, the septum structure of Staphylococcus warneri is extensively characterized using high-speed time-lapse confocal microscopy, atomic force microscopy, and electron

    更新日期:2020-05-24
  • Plexin-Bs enhance their GAP activity with a novel activation switch loop
    bioRxiv. Biophys. Pub Date : 2020-05-24
    ZHENLU LI; Jeannine Muller Greven; SoonJeung Kim; Luca Tamagnone; Matthias Buck

    Plexins receive guidance cues from semaphorin ligands and transmit their signal through the plasma membrane. This family of proteins is unique amongst single-pass transmembrane receptors as their intracellular regions interact directly with several small GTPases, which regulate cytoskeletal dynamics and cell adhesion. Here, we characterize the GTPase Activating Protein (GAP) function of Plexin-B1 and

    更新日期:2020-05-24
  • Atomic force microscopy visualizes mobility of photosynthetic proteins in grana thylakoid membranes
    bioRxiv. Biophys. Pub Date : 2020-05-24
    Bibiana Onoa; Shingo Fukuda; Masakazu Iwai; Carlos Bustamante; Krishna K Niyogi

    Thylakoid membranes in chloroplasts contain photosynthetic protein complexes that convert light energy into chemical energy. Photosynthetic protein complexes are considered to undergo structural reorganization to maintain the efficiency of photochemical reactions. A detailed description of the mobility of photosynthetic complexes in real-time is necessary to understand how macromolecular organization

    更新日期:2020-05-24
  • Mechanical cell competition in heterogeneous epithelial tissues
    bioRxiv. Biophys. Pub Date : 2020-05-24
    Ryan J Murphy; Pascal R Buenzli; Ruth E Baker; Matthew J Simpson

    Mechanical cell competition is important during tissue development, cancer invasion, and tissue ageing. Heterogeneity plays a key role in practical applications since cancer cells can have different cell stiffness and different proliferation rates than normal cells. To study this phenomenon, we propose a one-dimensional mechanical model of heterogeneous epithelial tissue dynamics that includes cell-length-dependent

    更新日期:2020-05-24
  • Proofreading through spatial gradients
    bioRxiv. Biophys. Pub Date : 2020-05-24
    Vahe Galstyan; Kabir Husain; Fangzhou Xiao; Arvind Murugan; Rob Phillips

    Key enzymatic processes in biology use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. Kinetic proofreading typically requires several dedicated structural features in the enzyme, such as a nucleotide hydrolysis site and multiple enzyme-substrate conformations that delay product formation. Such requirements limit the applicability and the adaptability

    更新日期:2020-05-24
  • A viral genome packaging motor transitions between cyclic and helical symmetry to translocate dsDNA
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Michael Woodson; Joshua Pajak; Wei Zhao; Wei Zhang; Gaurav Arya; Mark A White; Paul J Jardine; Marc C Morais

    Molecular segregation and biopolymer manipulation require the action of molecular motors to do work by applying directional forces to macromolecules. The additional strand conserved E (ASCE) ring motors are an ancient family of molecular motors responsible for diverse tasks ranging from biological polymer manipulation (e.g. protein degradation and chromosome segregation) to establishing and maintaining

    更新日期:2020-05-23
  • Actin binding domain of Rng2 sparsely bound on F-actin strongly inhibits actin movement on myosin II
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Yuuki Hayakawa; Masak Takaine; Taiga Imai; Masafumi Yamada; Keiko Hirose; Kien Xuan Ngo; Noriyuki Kodera; Kiyotaka Tokuraku; Osamu Numata; Kentaro Nakano; Taro Uyeda

    The contraction of contractile rings (CRs) depends on interaction between actin filaments and myosin II filaments. The rate of contraction in the fission yeast Schizosaccharomyces pombe is less than 1/120 of the velocity of acto-myosin II movement in vitro, but the mechanism of inhibition has not been described. Here, we found that the calponin-homology actin binding domain of fission yeast IQGAP Rng2

    更新日期:2020-05-23
  • Cadherin clusters stabilized by a combination of specific and nonspecific Cis-Interactions
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Connor J. Thompson; Zhaoqian Su; Vinh H. Vu; Yinghao Wu; Deborah E Leckband; Daniel K Schwartz

    We demonstrate a combined experimental and computational approach for the quantitative characterization of lateral interactions between membrane-associated proteins. In particular, weak, lateral (cis) interactions between E-cadherin extracellular domains tethered to supported lipid bilayers, were studied using a combination of dynamic single-molecule Förster Resonance Energy Transfer (FRET) and kinetic

    更新日期:2020-05-23
  • How and why plants and humans N-glycans are different: Insight from molecular dynamics into the "glycoblocks" architecture of complex carbohydrates
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Carl Aaron Fogarty; Aoife Martha Harbison; Amy Rebecca Dugdale; Elisa Fadda

    N-glycosylation is one of the most abundant and diverse post-translational modifications of proteins, implicated in protein folding and structural stability, and mediating interactions with receptors and with the environment. All N-glycans share a common core from which linear or branched arms stem from, with functionalization specific to different species and to the cells' health and disease state

    更新日期:2020-05-23
  • Detection of a multi-disease biomarker in Saliva with Graphene Field Effect Transistors
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Narendra Kumar; Mason Gray; Juan C. Ortiz-Marquez; Andrew Weber; Cameron R Desmond; Avni Argun; Tim van Opijnen; Kenneth S Burch

    Human carbonic anhydrase 1 (CA1) has been suggested as a biomarker for identification of several diseases including cancers, pancreatitis, diabetes, and Sjogren's syndrome. However, the lack of a rapid, cheap, accurate, and easy-to-use quantifcation technique has prevented widespread utilization of CA1 for practical clinical applications. To this end, we present a label-free electronic biosensor for

    更新日期:2020-05-23
  • Epithelial Cell-like Elasticity Modulates E-cadherin Adhesion Organization
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Mohamad Eftekharjoo; Siddharth Chatterji; Venkat Maruthamuthu

    E-cadherin adhesions are essential for cell-to-cell cohesion and mechanical coupling between epithelial cells and reside in a micro-environment that comprises the adjoining epithelial cells. While E-cadherin has been shown to be a mechanosensor, it is unknown if E-cadherin adhesions can differentially sense stiffness within the range of that of epithelial cells. A survey of literature shows that epithelial

    更新日期:2020-05-23
  • How to quantitatively measure, assess and correct the fluorescence crosstalk in the wide-field microscopy
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Hieng Chiong Tie; Lei Lu

    During the multi-color fluorescence imaging, a fluorophore can be detected in the non-corresponding channel due to the broad spectra of the fluorophore and filters, resulting in the artefact called the crosstalk (crossover or bleed-through). Unfortunately, the fluorescence crosstalk is ubiquitous for the conventional fluorescence microscopy. Significant crosstalk can distort the image and lead to incorrect

    更新日期:2020-05-23
  • Quantification of the Resilience and Vulnerability of HIV-1 Native Glycan Shield at Atomistic Detail
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Srirupa Chakraborty; Zachary T. Berndsen; Nicolas W. Hengartner; Bette T. Korber; Andrew B. Ward; S. Gnanakaran

    Dense surface glycosylation on the HIV-1 envelope (Env) protein acts as a shield from the adaptive immune system. However, the molecular complexity and flexibility of glycans make experimental studies a challenge. Here we have integrated high-throughput atomistic modeling of fully glycosylated HIV-1 Env with graph theory to capture immunologically important features of the shield topology. This is

    更新日期:2020-05-23
  • Exploring the Sequence Fitness Landscape of a Bridge Between Protein Folds
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Pengfei Tian; Robert B Best

    Most foldable protein sequences adopt only a single native fold. Recent protein design studies have, however, created protein sequences which fold into different structures apon changes of environment, or single point mutation, the best characterized example being the switch between the folds of the GA and GB binding domains of streptococcal protein G. To obtain further insight into the design of sequences

    更新日期:2020-05-23
  • Handhold-mediated strand displacement: a nucleic acid-based mechanism for generating far-from-equilibrium assemblies through templated reactions
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Javier Cabello-Garcia; Wooli Bae; Guy-Bart V Stan; Thomas E Ouldridge

    Toehold-mediated strand displacement (TMSD) is a nucleic acid-based reaction wherein an invader strand (I) replaces an incumbent strand (N) in a duplex with a target strand (T). TMSD is driven by toeholds, overhanging single-stranded domains in T recognised by I. Although TMSD is responsible for the outstanding potential of dynamic DNA nanotechnology, TMSD cannot implement templating, the central mechanism

    更新日期:2020-05-23
  • An RNA dynamic ensemble at atomic resolution
    bioRxiv. Biophys. Pub Date : 2020-05-23
    Honglue Shi; Atul Rangadurai; Hala Abou Assi; Rohit Roy; David A Case; Daniel Herschlag; Joseph D Yesselman; Hashim M Al-Hashimi

    Biomolecules do not fold into a single 3D structure but rather form dynamic ensembles of many inter-converting conformations. Knowledge of dynamic ensembles is key for understanding how biomolecules fold and function, and for rationally manipulating their activities in drug discovery and synthetic biology. However, solving dynamic ensembles of biomolecules at atomic resolution is a major challenge

    更新日期:2020-05-23
  • A DNA translocase operates by cycling between planar and lock-washer structures
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Juan P. Castillo; Alexander Tong; Sara Tafoya; Paul J. Jardine; Carlos Bustamante

    Ring ATPases that translocate disordered polymers possess lock-washer architectures that they impose on their substrates during transport via a hand-over-hand mechanism. Here, we investigate the operation of ring motors that transport substrates possessing a preexisting helical structure, such as the bacteriophage φ29 dsDNA packaging motor. During each cycle, this pentameric motor tracks one helix

    更新日期:2020-05-22
  • Single-particle cryo-EM at atomic resolution
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Takanori Nakane; Abhay Kotecha; Andrija Sente; Greg McMullan; Simonas Masiulis; Patricia M.G.E. Brown; Ioana T. Grigoras; Lina Malinauskaite; Tomas Malinauskas; Jonas Miehling; Lingbo Yu; Dimple Karia; Evgeniya V. Pechnikova; Erwin de Jong; Jeroen Keizer; Maarten Bischoff; Jamie McCormack; Peter Tiemeijer; Steven W. Hardwick; Dimitri Y. Chirgadze; Garib Murshudov; A. Radu Aricescu; Sjors Scheres

    The three-dimensional positions of atoms in protein molecules define their structure and provide mechanistic insights into the roles they perform in complex biological processes. The more precisely atomic coordinates are determined, the more chemical information can be derived and the more knowledge about protein function may be inferred. With breakthroughs in electron detection and image processing

    更新日期:2020-05-22
  • A Biophysical Model for Plant Cell Plate Development
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Muhammad Zaki Jawaid; Georgia Drakakaki; Rosalie M Sinclair; Daniel Cox

    Plant cell division involves de novo formation of a cell plate that partitions the cytoplasm of the dividing cell. Cell plate formation is directed by orchestrated delivery of cytokinetic vesicles via the phragmoplast, vesicle fusion, and membrane maturation to the nascent cell wall by the timely deposition of polysaccharides such as callose, cellulose, and crosslinking glycans. In contrast to the

    更新日期:2020-05-22
  • From Hi-C Contact Map to Three-dimensional Organization of Interphase Human Chromosomes
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Guang Shi; Dave Thirumalai

    The probabilities that two loci in chromosomes that are separated by a certain genome length can be inferred using chromosome conformation capture method and related Hi-C experiments. How to go from such maps to an ensemble of three-dimensional structures, which is an important step in understanding the way nature has solved the packaging of the hundreds of million base pair chromosomes in tight spaces

    更新日期:2020-05-22
  • Structural Features and Oligomeric Nature of Human Podocin Domain
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Sandeep Kuma Kumar Mulukala Narasimha; Shivkumar S Irukuvajjula; Krishan Kumar; Kanchan Garai; Pannuru Venkatesu; Ramakrishna Vadrevu; Anil kumar Pasupulati

    Podocytes are crucial cells of the glomerular filtration unit and playing a vital role at the interface of the blood-urine barrier. Podocyte slit-diaphragm is a modified tight junction that facilitates size and shape-dependent permselectivity. Several proteins including podocin, nephrin, CD2AP, and TRPC6 form a macromolecular assembly and constitute the slit-diaphragm. Podocin is an integral membrane

    更新日期:2020-05-22
  • Membrane bending by protein phase separation
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Feng Yuan; Haleh Alimohamadi; Brandon Bakka; Andrea N. Trementozzi; Nicolas L. Fawzi; Padmini Rangamani; Jeanne C. Stachowiak

    Membrane bending is a ubiquitous cellular process that is required for membrane traffic, cell motility, organelle biogenesis, and cell division. Proteins that bind to membranes using specific structural features, such as wedge-like amphipathic helices and crescent-shaped scaffolds, are thought to be the primary drivers of membrane bending. However, many membrane-binding proteins have substantial regions

    更新日期:2020-05-22
  • Intrinsic disorder in the T cell receptor creates cooperativity and controls ZAP70 binding
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Lara Clemens; Omer Dushek; Jun F Allard

    Many immunoreceptors have cytoplasmic domains that are intrinsically disordered (i.e., have high configurational entropy), have multiple sites of post-translational modification (e.g., tyrosine phosphorylation), and participate in nonlinear signaling pathways (e.g., exhibiting switch-like behavior). Several hypotheses to explain the origin of these nonlinearities fall under the broad hypothesis that

    更新日期:2020-05-22
  • COX-1 - lipid interactions: arachidonic acid, cholesterol, and phospholipid binding to the membrane binding domain of COX-1
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Besian I. Sejdiu; D. Peter Tieleman

    Cyclooxygenases carry out the committed step in prostaglandin synthesis and are the target of NSAIDs, the most widely used class of drugs in alleviating pain, fever, and inflammation. While extensively studied, one aspect of their biology that has been neglected is their interaction with membrane lipids. Such lipid-protein interactions have been shown to be a driving force behind membrane protein function

    更新日期:2020-05-22
  • Stretched-Exponential Modeling of Anomalous T1ρ and T2 Relaxation in the Intervertebral Disc In Vivo
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Robert Wilson; Leah Bowen; Woong Kim; David Reiter; Corey Neu

    Purpose: Intervertebral disc degeneration (IVDD), resulting in the depletion of hydrophilic glycosaminoglycans (GAGs) located in the nucleus pulposus (NP), can lead to debilitating neck and back pain. Magnetic Resonance Imaging (MRI) is a promising means of IVD assessment due to the sensitivity of MRI tissue relaxation properties to matrix composition. Furthermore, anomalous (i.e. non-monoexponential)

    更新日期:2020-05-22
  • A mechanistic model improves off-target predictions and reveals the physical basis of SpCas9 fidelity
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Behrouz Eslami-Mossallam; Misha Klein; Constantijn van der Smagt; Koen van der Sanden; Stephen K Jones; John A Hawkins; Ilya J Finkelstein; Martin Depken

    The SpCas9 endonuclease has become an important tool in gene-editing and basic science alike. Though easily programmed to target any sequence, SpCas9 also shows considerable activity over genomic off-targets. Many empirical facts regarding the targeting reaction have been established, but a comprehensive mechanistic description is still lacking - limiting fundamental understanding, our ability to predict

    更新日期:2020-05-22
  • Structural Ensembles of Ribonucleic Acids From Solvent Accessibility Data: Application to the S-Adenosylmethionine (SAM)-Responsive Riboswitch
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Jingru Xie; Aaron Terrence Frank

    Riboswitches are regulatory ribonucleic acid (RNA) elements that act as ligand-dependent conformational switches. In the apo form, the aptamer domain, the region of a riboswitch that binds to its cognate ligand, is dynamic, thus requiring an ensemble-representation of its structure. Analysis of such ensembles can provide molecular insights into the sensing mechanism and capabilities of riboswitches

    更新日期:2020-05-22
  • Traction Force Microscopy by Deep Learning
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Yu-Li Wang; Yun-Chu Lin

    Cells interact mechanically with their surrounding by exerting forces and sensing forces or force-induced displacements. Traction force microscopy (TFM), purported to map cell-generated forces or stresses, represents an important tool that has powered the rapid advances in mechanobiology. However, to solve the ill-posted mathematical problem, its implementation has involved regularization and the associated

    更新日期:2020-05-22
  • Viscoelasticity of single macromolecules using Atomic Force Microscopy
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Shivprasad Patil Vitthal Patil; Shatruhan S Rajput; Suryapratap deopa; Jyoti Yadav; Vikhyaat Ahlawat; Saurabh Talele

    We measured viscoelasticity of single protein molecules using two types of Atomic Force Microscopes (AFM) which employ different detection schemes to measure the cantilever response. We used a commonly available deflection detection scheme in commercial AFMs which measures cantilever bending and a fibre-interferometer based home-built AFM which measures cantilever displacement. For both methods, the

    更新日期:2020-05-22
  • Selective inhibition of human translation by a drug-like compound that traps terminated protein nascent chains on the ribosome
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Wenfei Li; Stacey T.-L. Chang; Fred R. Ward; Jamie H. D. Cate

    Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF- 06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation

    更新日期:2020-05-22
  • Minimal biophysical model of combined antibiotic action
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Bor Kavčič; Gašper Tkačik; Tobias Bollenbach

    Phenomenological relations such as Ohm's or Fourier's law have a venerable history in physics, but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial "growth laws," which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts

    更新日期:2020-05-22
  • Single Molecule Light Field Microscopy
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Ruth R Sims; Sohaib Abdul Rehman; Martin O Lenz; Adam Clark; Edward W Sanders; Aleks Ponjavic; Leila Muresan; Steven F Lee; Kevin O'Holleran

    We introduce single molecule light field microscopy (SMLFM), a novel 3D single molecule localization technique that is capable of up to 20 nm isotropic precision across a 6 μm depth of field. SMLFM can be readily implemented by installing a refractive microlens array into the conjugate back focal plane of any widefield single molecule localization system. We demonstrate that 3D localization can be

    更新日期:2020-05-22
  • Breaking the next Cryo-EM resolution barrier - Atomic resolution determination of proteins!
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Ka Man Yip; Niels Fischer; Elham Paknia; Ashwin Chari; Holger Stark

    Single particle cryo-EM is a powerful method to solve the three-dimensional structures of biological macromolecules. The technological development of electron microscopes, detectors, automated procedures in combination with user friendly image processing software and ever-increasing computational power have made cryo-EM a successful and largely expanding technology over the last decade. At resolutions

    更新日期:2020-05-22
  • Fluctuation spectroscopy of giant unilamellar vesicles using confocal and phase contrast microscopy
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Hammad A. Faizi; Cody J. Reeves; Vasil N. Georgiev; Petia M. Vlahovska; Rumiana Dimova

    A widely used method to measure the bending rigidity of bilayer membranes is fluctuation spectroscopy, which analyses the thermally-driven membrane undulations of giant unilamellar vesicles recorded with either phase-contrast or confocal microscopy. Here, we analyze the fluctuations of the same vesicle using both techniques and obtain consistent values for the bending modulus. We discuss the factors

    更新日期:2020-05-22
  • First passage time study of DNA strand displacement
    bioRxiv. Biophys. Pub Date : 2020-05-22
    D. W. Bo Broadwater; Alexander W. Cook; Harold D. Kim

    DNA strand displacement, where a single-stranded nucleic acid invades a DNA duplex, is pervasive in genomic processes and DNA engineering applications. The kinetics of strand displacement have been studied in bulk; however, the kinetics of the underlying strand exchange were obfuscated by a slow bimolecular association step. Here, we use a novel single-molecule Fluorescence Resonance Energy Transfer

    更新日期:2020-05-22
  • Nonallosteric Sirtuin Enzyme Activation: Characterization of Hit Compounds
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Alok Upadhyay; Xiangying Guan; Sudipto Munshi; Raj Chakrabarti

    Mammalian sirtuins (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play critical roles in lifespan and age-related diseases. The physiological importance of sirtuins has stimulated intense interest in designing sirtuin-activating compounds. However, except for allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates

    更新日期:2020-05-22
  • Molecular dynamics simulations of protein aggregation: protocols for simulation setup and analysis with Markov state models and transition networks
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Suman Samantray; Wibke Schumann; Alexander-Maurice Illig; Martin Carballo-Pacheco; Arghadwip Paul; Bogdan Barz; Birgit Strodel

    Protein disorder and aggregation play significant roles in the pathogenesis of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The end products of the aggregation process in these diseases are β-sheet rich amyloid fibrils. Though in most cases small, soluble oligomers formed during amyloid aggregation are the toxic species. A full understanding of the physicochemical

    更新日期:2020-05-22
  • StormGraph: A graph-based algorithm for quantitative clustering analysis of heterogeneous single-molecule localization microscopy data
    bioRxiv. Biophys. Pub Date : 2020-05-22
    Joshua Scurll; Libin Abraham; Da Wei Zheng; Reza Tafteh; Keng Chou; Michael R Gold; Daniel Coombs

    Clustering of proteins is crucial for many cellular processes and can be imaged at nanoscale resolution using single-molecule localization microscopy (SMLM). Existing cluster analysis methods for regions of interest (ROIs) from SMLM data suffer from major limitations, such as unsuitability for heterogeneous datasets, failure to account for uncertainties in localization data, inability to analyze 3D

    更新日期:2020-05-22
  • Computational Analysis of Dynamic Allostery and Control in the SARS-CoV-2 Main Protease
    bioRxiv. Biophys. Pub Date : 2020-05-21
    Tom C McLeish; Igors Dubanevics

    The dynamics and thermodynamics of the homodimer main protease protein SARS-CoV-2 are analysed at the level of Elastic Network Models (ENM). Correlated motions display a rich and heterogeneous dynamical structure, including allosterically correlated motions between the active sites in the two domains. Exhaustive 1-point and 2-point mutation maps, and their effect on binding free energies and allosteric

    更新日期:2020-05-21
  • Modeling and Simulation of a Fully-glycosylated Full-length SARS-CoV-2 Spike Protein in a Viral Membrane
    bioRxiv. Biophys. Pub Date : 2020-05-21
    Hyeonuk Woo; Sang-Jun Park; Yeol Kyo Choi; Taeyong Park; Maham Tanveer; Yiwei Cao; Nathan R Kern; Jumin Lee; Min Sun Yeom; Tristan Croll; Chaok Seok; Wonpil Im

    This technical study describes all-atom modeling and simulation of a fully-glycosylated full-length SARS-CoV-2 spike (S) protein in a viral membrane. First, starting from PDB:6VSB and 6VXX, full-length S protein structures were modeled using template-based modeling, de-novo protein structure prediction, and loop modeling techniques in GALAXY modeling suite. Then, using the recently-determined most

    更新日期:2020-05-21
  • Coordinating cell polarization and morphogenesis through mechanical feedback
    bioRxiv. Biophys. Pub Date : 2020-05-21
    Samhita P Banavar; Michael Trogdon; Brian Drawert; Tau-Mu Yi; Linda R Petzold; Otger Campas

    Many cellular processes require cell polarization to be maintained as the cell changes shape, grows or moves. Without feedback mechanisms relaying information about cell shape to the polarity molecular machinery, the coordination between cell polarization and morphogenesis, movement or growth would not be possible. Here we theoretically and computationally study the role of a genetically-encoded mechanical

    更新日期:2020-05-21
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