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  • Ebselen Reacts with SARS Coronavirus-2 Main Protease Crystals
    bioRxiv. Biophys. Pub Date : 2020-08-10
    Tek Narsingh Malla; Suraj Pandey; Ishwor Poudyal; Denisse Feliz; Moraima Noda; George Phillips; Emina Stojkovic; Marius Schmidt

    The SARS coronavirus 2 main protease 3CLpro tailor cuts various essential virus proteins out of long poly-protein translated from the virus RNA. If the 3CLpro is inhibited, the functional virus proteins cannot form and the virus cannot replicate and assemble. Any compound that inhibits the 3CLpro is therefore a potential drug to end the pandemic. Here we show that the diffraction power of 3CLpro crystals

    更新日期:2020-08-11
  • TRPV2 interaction with small molecules and lipids revealed by cryo-EM
    bioRxiv. Biophys. Pub Date : 2020-08-10
    Anna D. Protopopova; Ruth A. Pumroy; Jeanne de la Roche; Ferdinand M. Haug; Barbara B. Sousa; Pamela N. Gallo; Goncalo J.L. Bernardes; Andreas Leffler; Vera Moiseenkova-Bell

    Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in a variety of physiological and pathophysiological processes, putting TRPV2 on the list of important drug targets. Yet, specific TRPV2 agonists and antagonists are currently unavailable. Their development requires a precise knowledge of how the currently known non-specific small molecules interact with TRPV2 at the molecular level

    更新日期:2020-08-11
  • DEER-PREdict: Software for Efficient Calculation of Spin-Labeling EPR and NMR Data from Conformational Ensembles
    bioRxiv. Biophys. Pub Date : 2020-08-10
    Giulio Tesei; Joao M Martins; Micha B.A. Kunze; Yong Wang; Ramon Crehuet; Kresten Lindorff-Larsen

    Owing to their plasticity, intrinsically disordered and multidomain proteins require descriptions based on multiple conformations, thus calling for techniques and analysis tools that are capable of dealing with conformational ensembles rather than a single protein structure. Here, we introduce DEER-PREdict, a software to predict Double Electron-Electron Resonance distance distributions as well as Paramagnetic

    更新日期:2020-08-11
  • Two modes of PRC1-mediated mechanical resistance to kinesin-driven microtubule network disruption
    bioRxiv. Biophys. Pub Date : 2020-08-10
    April Alfieri; Ignas Gaska; Scott Forth

    The proper structural organization of the microtubule-based spindle during cell division requires the collective activity of many different types of proteins. These include non-motor microtubule-associated proteins (MAPs) whose functions include crosslinking microtubules to regulate filament sliding rates and assembling microtubule arrays. One such protein is PRC1, an essential MAP that has been shown

    更新日期:2020-08-11
  • Computational Tool for Ensemble Averaging of Single-Molecule Data
    bioRxiv. Biophys. Pub Date : 2020-08-10
    Thomas J Blackwell; W Tom Stump; Sarah R Clippinger; Michael J Greenberg

    Molecular motors couple chemical transitions to conformational changes that perform mechanical work in a wide variety of biological processes. Disruption of this coupling can lead to diseases, and therefore there is a need to accurately measure mechanochemical coupling in motors in both health and disease. Optical tweezers, with nanometer spatial and millisecond temporal resolution, have provided valuable

    更新日期:2020-08-11
  • Membrane composition and lipid to protein ratio modulate amyloid kinetics of yeast prion protein
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Krishnananda Chattopadhyay; Achinta Sannigrahi; Arnab Bandyopadhyay

    Understanding of prion aggregation in membrane environment may help to ameliorate neurodegenerative complications caused by the amyloid forms of prions. Here, we investigated the membrane binding induced aggregation of yeast prion protein Sup35. Using the combination of fluorescence correlation spectroscopy (FCS) at single molecule resolution and other biophysical studies, we establish that lipid composition

    更新日期:2020-08-10
  • Single-molecule studies of conformational states and dynamics in the ABC importer OpuA
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Konstantinos Tassis; Ruslan Vietrov; Matthijs de Koning; Marijn de Boer; Giorgos Gouridis; Thorben Cordes

    The current model of active transport via ABC importers is mostly based on structural, biochemical and genetic data. We here establish single-molecule Foerster-resonance energy transfer (smFRET) assays to monitor the conformational states and heterogeneity of the type-I ABC importer OpuA from Lactococcus lactis. Our studies include intradomain assays that elucidate conformational changes within the

    更新日期:2020-08-10
  • Theory of genetic oscillations with external noisy regulation
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Jose Negrete; Ivan Miguel Lengyel; Laurel Rohde; Ravi A Desai; Andrew C Oates; Frank Julicher

    We present a general theory of noisy genetic oscillators with externally regulated production rate. The observables that characterize the genetic oscillator are discussed, and it is shown how their statistics depend on the statistics of the external regulator. We show that these observables have generic features that are observed in two different experimental systems: the expression of the circadian

    更新日期:2020-08-10
  • Multivalent interactions between eIF4G1, Pub1 and Pab1 drive the formation of protein condensates
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Belén Chaves-Arquero; Santiago Martínez-Lumbreras; Nathalie Sibille; Sergio Camero; Pau Bernadó; María Ángeles Jiménez; Silvia Zorrilla; José Manuel Pérez-Cañadillas

    Yeast eIF4G1 interacts with RNA binding proteins (RBPs) like Pab1 and Pub1 affecting its function in translation initiation and stress granules formation. We present an NMR and SAXS study of the intrinsically disordered region of eIF4G1, eIF4G11-249, and its interactions with Pub1 and Pab1. The conformational ensemble of eIF4G11-249 shows an α-helix within the BOX3 conserved element and a dynamic network

    更新日期:2020-08-08
  • Ribosome fingerprinting with a solid-state nanopore
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Mukhil Raveendran; Anna Rose Leach; Tayah S Hopes; Julie Aspden; Paolo Actis

    Nanopores hold great potential for the analysis of complex biological molecules at the single entity level. One particularly interesting macromolecular machine is the ribosome, responsible for translating mRNA into proteins. In this study, we use a solid-state nanopore to fingerprint 80S ribosomes and polysomes from a human neuronal cell line and, Drosophila melanogaster cultured cells and ovaries

    更新日期:2020-08-08
  • Proteins and Ions Compete for Membrane Interaction: the case of Lactadherin
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Ashley Marie De Lio; Diviyani Paul; Riya Jain; James H Morrissey; Taras V Pogorelov

    Charged molecular species, such as ions, play a vital role in the life of the cell. In particular, divalent calcium ions (Ca2+) are critical for activating cellular membranes. Interactions between Ca2+ and anionic phosphatidylserine (PS) lipids result in structural changes of the plasma membrane and are vital for many signaling pathways, such as the tightly regulated blood coagulation cascade. Upon

    更新日期:2020-08-08
  • Bound2Learn: A Machine Learning Approach for Classification of DNA-Bound Proteins from Single-Molecule Tracking Experiments
    bioRxiv. Biophys. Pub Date : 2020-08-07
    Nitin Kapadia; Ziad W El-Hajj; RODRIGO REYES LAMOTHE

    Many proteins act on DNA for a wide range of processes, including DNA replication, DNA repair, and transcription. Their time spent on DNA can provide insight into these processes and their stability within complexes to which they may belong. Single-particle tracking allows for direct visualization of protein-DNA kinetics, however, identifying whether a molecule is bound to DNA can be non-trivial. Further

    更新日期:2020-08-08
  • CorRelator: An interactive and flexible toolkit for high-precision cryo-correlative light and electron microscopy
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Jie E Yang; Matthew R Larson; Bryan S Sibert; Samantha Shrum; Elizabeth R Wright

    Cryo-correlative light and electron microscopy (CLEM) is a technique that uses the spatiotemporal cues from fluorescence light microscopy (FLM) to investigate the high-resolution ultrastructure of biological samples by cryo-electron microscopy (cryo-EM). Cryo-CLEM provides advantages for identifying and distinguishing fluorescently labeled proteins, macromolecular complexes, and organelles from the

    更新日期:2020-08-08
  • Data-guided Multi-Map variables for ensemble refinement of molecular movies
    bioRxiv. Biophys. Pub Date : 2020-08-06
    John W Vant; Daipayan Sarkar; Giacomo Fiorin; Robert D. Skeel; Josh V. Vermaas; Abhishek Singharoy

    Driving molecular dynamics simulations with data-guided collective variables offer a promising strategy to recover thermodynamic information from structure-centric experiments. Here, the 3-dimensional electron density of a protein, as it would be deter- mined by cryo-EM or X-ray crystallography, is used to achieve simultaneously free-energy costs of conformational transitions and refined atomic structures

    更新日期:2020-08-08
  • Ripples at edges of blooming lilies and torn plastic sheets
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Thomas Portet; Peter N. Holmes; Sarah L Keller

    Ripples arise at edges of petals of blooming Lilium casablanca flowers and at edges of torn plastic sheets. In both systems, ripples are a consequence of excess length along the edge of a sheet. Through the use of both time-lapse videos of blooming lilies and still images of torn plastic sheets, we find that ripples in both systems are well-described by the scaling relationship a ∝ √(w(L − w)), where

    更新日期:2020-08-08
  • Continuous Constant pH Molecular Dynamics of Transmembrane Proteins
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Yandong Huang; Jack A. Henderson; Jana Shen

    Many membrane channels, transporters, and receptors utilize a pH gradient or proton coupling to drive functionally relevant conformational transitions. Conventional molecular dynamics simulations employ fixed protonation states, thus neglecting the coupling between protonation and conformational equilibria. Here we describe the membrane-enabled hybrid-solvent continuous constant pH molecular dynamics

    更新日期:2020-08-08
  • Predicting in vivo escape dynamics of HIV-1 from a broadly neutralizing antibody
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Matthijs Meijers; Kanika Vanshylla; Henning Gruell; Florian Klein; Michael Laessig

    Broadly neutralizing antibodies are promising candidates for treatment and prevention of HIV-1 infections. Such antibodies can temporarily suppress viral load in infected individuals; however, the virus often rebounds by escape mutants that have evolved resistance. In this paper, we map an in vivo fitness landscape of HIV-1 interacting with broadly neutralizing antibodies, using data from a recent

    更新日期:2020-08-08
  • The emergence of phase separation as an organizing principle in bacteria
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Christopher A. Azaldegui; Anthony G Vecchiarelli; Julie Suzanne Biteen

    Recent investigations in bacteria suggest that membraneless organelles play a crucial role in the subcellular organization of bacterial cells. However, the biochemical functions and assembly mechanisms of these compartments have not yet been completely characterized. This Review assesses the current methodologies used in the study of membraneless organelles in bacteria, highlights the limitations in

    更新日期:2020-08-08
  • Thermodynamics of DNA Hybridization from Atomistic Simulations
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Gul Zerze; Frank Stillinger; Pablo Debenedetti

    Studying the DNA hybridization equilibrium via brute force molecular dynamics (MD) or commonly used advanced sampling approaches is notoriously difficult at the atomistic length scale. However, besides providing more realistic modeling of this microscopic phenomenon, the atomistic resolution is a necessity for some fundamental research questions, such as the ones related to DNA's chirality. Here, we

    更新日期:2020-08-08
  • Investigating the effects of molecular crowding on the kinetics of protein aggregation
    bioRxiv. Biophys. Pub Date : 2020-08-06
    John S Schreck; John Bridstrup; Jian-Min Yuan

    The thermodynamics and kinetics of protein folding and protein aggregation in vivo are of great importance in numerous scientific areas including fundamental biophysics research, nanotechnology, and medicine. However, these processes remain poorly understood in both in vivo and in vitro systems. Here we extend an established model for protein aggregation that is based on the kinetic equations for the

    更新日期:2020-08-08
  • Signatures and mechanisms of efficacious therapeutic ribonucleotides against SARS-CoV-2 revealed by analysis of its replicase using magnetic tweezers
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Mona Seifert; Subhas C. Bera; Pauline van Nies; Robert N. Kirchdoerfer; Ashleigh Shannon; Thi-Tuyet-Nhung Le; Tyler L. Grove; Flavia S. Papini; Jamie J. Arnold; Steven C. Almo; Bruno Canard; Martin Depken; Craig E. Cameron; David Dulin

    Coronavirus Disease 2019 (COVID-19) results from an infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the third coronavirus outbreak to plague humanity this century. Currently, the most efficacious therapeutic against SARS-CoV-2 infection is the Remdesivir (RDV), an adenine-like ribonucleotide analogue that is very efficiently incorporated by the SARS-CoV-2 replicase. Understanding

    更新日期:2020-08-08
  • Computational Hot-Spot Analysis of the SARS-CoV-2 Receptor Binding Domain / ACE2 Complex
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Pedro A. Rosario; Brian R McNaughton

    Infection and replication of SARS CoV-2 (the virus that causes COVID-19) requires entry to the interior of host cells. In humans, a Protein-Protein Interaction (PPI) between the SARS CoV-2 Receptor-Binding Domain (RBD) and the extracellular peptidase domain of ACE2, on the surface of cells in the lower respiratory tract, is an initial step in the entry pathway. Inhibition of the SARS CoV-2 RBD / ACE2

    更新日期:2020-08-08
  • Liquid-liquid phase separation of tau driven by hydrophobic interaction facilitates fibrillization of tau
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Yanxian Lin; Yann Fichou; Andrew P. Longhini; Luana C. Llanes; Yinson Yin; Guillermo C. Bazan; Kenneth S Kosik; Songi Han

    Amyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) both in vivo and in vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while independent of aggregation in other cases. It is therefore important to understand the

    更新日期:2020-08-06
  • PI3K inhibition reverses migratory direction of single cells but not cell groups in electric field
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Yaohui Sun; Haicen Yue; Calina Copos; Kan Zhu; Yang Zhang; Xing Gao; Yuxin Sun; Brian Reid; Francis Lin; Min Zhao; Alex Mogilner

    Motile cells migrate directionally in the electric field in a process known as galvanotaxis. Galvanotaxis is important in wound healing, development, cell division, and nerve growth. Different cell types migrate in opposite directions in electric fields, to either cathode, or anode, and the same cell can switch the directionality depending on chemical conditions. We previously reported that individual

    更新日期:2020-08-06
  • Molecular details of protein condensates probed by microsecond-long atomistic simulations
    bioRxiv. Biophys. Pub Date : 2020-08-06
    Wenwei Zheng; Gregory L Dignon; Xichen Xu; Roshan Mammen Regy; Nicolas L Fawzi; Young C Kim; Robert Best; Jeetain Mittal

    The formation of membraneless organelles in cells commonly occurs via liquid-liquid phase separation (LLPS), and is in many cases driven by multivalent interactions between intrinsically disordered proteins (IDPs). Molecular simulations can reveal the specific amino acid interactions driving LLPS, which is hard to obtain from experiment. Coarse-grained simulations have been used to directly observe

    更新日期:2020-08-06
  • Deciphering complex mechanisms of resistance and loss of potency through coupled molecular dynamics and machine learning.
    bioRxiv. Biophys. Pub Date : 2020-08-05
    Florian Leidner; Nese Kurt-Yilmaz; Celia A Schiffer

    Drug resistance threatens many critical therapeutics through mutations in the drug target. The molecular mechanisms by which combinations of mutations, especially involving those distal from the active site, alter drug binding to confer resistance are poorly understood and thus difficult to counteract. A machine learning strategy was developed that couples parallel molecular dynamics simulations and

    更新日期:2020-08-06
  • Epithelial Tissues as Active Solids: From Nonlinear Contraction Pulses to Rupture Resistance
    bioRxiv. Biophys. Pub Date : 2020-08-05
    Shahaf Armon; Matthew Storm Bull; Avraham Moriel; Hillel Aharoni; Manu Prakash

    Epithelial tissues in many contexts can be viewed as soft active solids. Their active nature is manifested in the ability of individual cells within the tissue to contract and/or remodel their mechanical properties in response to various conditions. Little is known about the emergent properties of such materials. Specifically, how an individual cellular activity gives rise to collective spatiotemporal

    更新日期:2020-08-06
  • Atomistic Mechanism of Force Generation, Translocation, and Coordination in a Viral Genome Packaging Motor
    bioRxiv. Biophys. Pub Date : 2020-08-04
    Joshua Pajak; Erik Dill; Mark A. White; Brian A. Kelch; Paul Jardine; Gaurav Arya; Marc C. Morais

    stranded DNA viruses package their genomes into pre-assembled protein capsids using virally-encoded ATPase ring motors. While several structures of isolated monomers (subunits) from these motors have been determined, they provide little insight into how subunits within a functional ring coordinate their activities to efficiently generate force and translocate DNA. Here we describe the first atomic-resolution

    更新日期:2020-08-05
  • Mitigation of radiation damage in macromolecules via tunable ultrafast stroboscopic TEM
    bioRxiv. Biophys. Pub Date : 2020-08-04
    Hyeokmin Choe; Ilya Ponomarev; Eric Montgomery; June W. Lau; Yimei Zhu; Yubin Zhao; Ao Liu; Alexei Kanareykin; Chunguang Jing

    We report mitigation of electron-beam-induced radiation damage in biological macromolecules using rapid, low-dose transmission electron microscopy (TEM) with a new, tunable, retrofittable stroboscopic pulser. Damage mitigation strategies historically consisted of sample cryoprotection and ultra-low beam current; ultrafast laser-pulsed systems have shown promise, but with day-long acquisition times

    更新日期:2020-08-05
  • Muscle activity of cutting manoeuvres and soccer inside passing suggests an increased groin injury risk during these movements
    bioRxiv. Biophys. Pub Date : 2020-08-04
    Thomas Dupré Julian Tryba; Wolfgang Potthast

    Cutting manoeuvres and inside passing are thought to increase the risk for sustaining groin injuries. But both movements and cutting manoeuvres in particular have received little research attention in this regard. The purpose of this study was to investigate the muscle activity of adductor longus and gracilis as well as hip and knee joint kinematics during 90 °-cutting and inside passing. Thirteen

    更新日期:2020-08-05
  • High-precision protein-tracking with interferometric scattering microscopy
    bioRxiv. Biophys. Pub Date : 2020-08-04
    Richard William Taylor; Cornelia Holler; Reza Gholami Mahmoodabadi; Michelle Küppers; Houman Mirzaalian Dastjerdi; Vasily Zaburdaev; Alexandra Schambony; Vahid Sandoghdar

    The mobility of proteins and lipids within the cell, sculpted often times by the organisation of the membrane, reveals a great wealth of information on the function and interaction of these molecules as well as the membrane itself. Single particle tracking has proven to be a vital tool to study the mobility of individual molecules and unravel details of their behaviour. Interferometric scattering (iSCAT)

    更新日期:2020-08-05
  • Addressing the Embeddability Problem in Transition Rate Estimation
    bioRxiv. Biophys. Pub Date : 2020-08-04
    Curtis Goolsby; Mahmoud Moradi

    Markov State Models (MSM) and related techniques have gained significant traction as a tool for analyzing and guiding molecular dynamics (MD) simulations due to their ability to extract structural, thermodynamic, and kinetic information on proteins using computationally feasible MD simulations. The MSM analysis often relies on spectral decomposition of empirically generated transition matrices. Here

    更新日期:2020-08-04
  • CryoFold: Ab-initio structure determination from electron density maps using molecular dynamics
    bioRxiv. Biophys. Pub Date : 2020-08-03
    Mrinal Shekhar; Genki Terashi; Chitrak Gupta; Daipayan Sarkar; Gaspard Debussche; Nicholas Sisco; Jonathan Nguyen; Arup Mondal; James Zook; John Vant; Petra Fromme; Wade D van Horn; Daisuke Kihara; Emad Tajkhorshid; Ken Dill; Alberto Perez; Abhishek Singharoy

    Cryo-EM is a powerful method for determining protein structures.But it requires computational assistance. Physics-based computations have the power to give low-free-energy structures and ensembles of populations, but have been computationally limited to only small soluble proteins. Here, we introduce CryoFold. By integrating data of varying sparsity from electron density maps of 3-5 A resolution with

    更新日期:2020-08-04
  • Mechanism of duplex unwinding by coronavirus nsp13 helicases
    bioRxiv. Biophys. Pub Date : 2020-08-03
    Xiao Hu; Wei Hao; Bo Qin; Zhiqi Tian; Ziheng Li; Pengjiao Hou; Rong Zhao; Sheng Cui; Jiajie Diao

    The current COVID-19 pandemic urges in-depth investigation into proteins encoded with coronavirus (CoV), especially conserved CoV replicases. The nsp13 of highly pathogenic MERS-CoV, SARS-CoV-2, and SARS-CoV exhibit the most conserved CoV replicases. Using single-molecule FRET, we observed that MERS-CoV nsp13 unwound DNA in discrete steps of approximately 9 bp when ATP was used. If another NTP was

    更新日期:2020-08-04
  • Circumventing the optical diffraction limit with customized speckles
    bioRxiv. Biophys. Pub Date : 2020-08-03
    Nicholas Bender; Mengyuan Sun; Hasan Yilmaz; Joerg Bewersdorf; Hui Cao

    Speckle patterns have been widely used in imaging techniques such as ghost imaging, dynamic speckle illumination microscopy, structured illumination microscopy, and photoacoustic fluctuation imaging. Recent advances in the ability to control the statistical properties of speckles has enabled the customization of speckle patterns for specific imaging applications. In this work, we design and create

    更新日期:2020-08-04
  • Cell cycle-dependent active stress drives epithelia remodeling
    bioRxiv. Biophys. Pub Date : 2020-07-31
    John Devany; Daniel M. Sussman; M. Lisa Manning; Margaret L. Gardel

    Epithelia have distinct cellular architectures, which are established in development, re-established after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here we investigate cell shape changes in a model epithelial monolayer.

    更新日期:2020-08-01
  • KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Timothy H. Tran; Albert H. Chan; Lucy C. Young; Lakshman Bindu; Christopher Neale; Simon Messing; Srisathiyanarayanan Dharmaiah; Troy Taylor; John-Paul Denson; Dominic Esposito; Dwight V. Nissley; Andrew G. Stephen; Frank McCormick; Dhirendra K Simanshu

    A vital first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we solved crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of

    更新日期:2020-08-01
  • High speed, three-dimensional imaging reveals chemotactic behavior specific to human-infective Leishmania parasites
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Rachel C Findlay; Mohamed Osman; Kirstin Spence; Paul M. Kaye; Pegine B. Walrad; Laurence G. Wilson

    Cellular motility is an ancient eukaryotic trait, ubiquitous across phyla with roles in predator avoidance, resource access and competition. Flagellar-dependent motility is seen in a variety of parasitic protozoans and morphological changes in flagellar structure and function have been qualitatively described during differentiation. However, whether the dynamics of flagellar motion vary across lifecycle

    更新日期:2020-08-01
  • Biomechanical Characterization of SARS-CoV-2 Spike RBD and Human ACE2 Protein-Protein Interaction
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Wenpeng Cao; Chuqiao Dong; Seonghan Kim; Decheng Hou; Wanbo Tai; Lanying Du; Wonpil Im; X. Frank Zhang

    The current COVID-19 pandemic has already had a devastating impact across the world. SARS-CoV-2 (the virus causing COVID-19) is known to use its surface spike (S) protein's receptor binding domain (RBD) to interact with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on many human cell types. The RBD–ACE2 interaction is a crucial step to mediate the host cell entry of SARS-CoV-2. Recent

    更新日期:2020-08-01
  • Comparative study of curvature sensing mediated by F-BAR domain and an intrinsically disordered region of FBP17
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Maohan Su; Yinyin Zhuang; Xinwen Miao; Yongpeng Zeng; Weibo Gao; Wenting Zhao; Min Wu

    Membrane curvature has emerged as an intriguing physical organization principle underlying biological signaling and membrane trafficking. FBP17 of the CIP4/FBP17/Toca-1 F-BAR family is unique in the BAR family because its structurally folded F-BAR domain does not contain any hydrophobic motifs that insert into lipid bilayer. While it has been widely assumed so, whether the banana-shaped F-BAR domain

    更新日期:2020-08-01
  • Force-dependent stimulation of RNA unwinding by SARS-CoV-2 nsp13 helicase
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Keith J Mickolajczyk; Patrick M M Shelton; Michael Grasso; Xiaocong Cao; Sara R Warrington; Amol Aher; Shixin Liu; Tarun M Kapoor

    The superfamily-1 helicase non-structural protein 13 (nsp13) is required for SARS-CoV-2 replication, making it an important antiviral therapeutic target. The mechanism and regulation of nsp13 has not been explored at the single-molecule level. Specifically, force-dependent unwinding experiments have yet to be performed for any coronavirus helicase. Here, using optical tweezers, we find that nsp13 unwinding

    更新日期:2020-08-01
  • Computer Simulations of the interaction between SARS-CoV-2 spike glycoprotein and different surfaces
    bioRxiv. Biophys. Pub Date : 2020-07-31
    David C Malaspina; Jordi Faraudo

    A prominent feature of coronaviruses is the presence of a large glycoprotein spike protruding from a lipidic membrane. This glycoprotein spike determines the interaction of coronaviruses with the environment and the host. In this paper, we perform all atomic Molecular Dynamics simulations of the interaction between the SARS-CoV-2 trimeric glycoprotein spike and surfaces of materials. We considered

    更新日期:2020-08-01
  • Glycine Rich Segments Adopt Polyproline II Helices Which May Contribute to Biomolecular Condensate Formation
    bioRxiv. Biophys. Pub Date : 2020-07-31
    Miguel Mompean; Bethan S. McAvan; Sara S. Felix; Miguel Trevino; Javier Oroz; David Pantoja-Uceda; Eurico J. Cabrita; Andrew J. Doig; Douglas Vinson Laurents

    Many intrinsically disordered proteins contain Gly-rich regions which are generally assumed to be disordered. Such regions often form biomolecular condensates which play essential roles in organizing cellular processes. However, the bases of their formation and stability are still not completely understood. Considering NMR studies of the Gly-rich H. harveyi "snow flea" antifreeze protein, we recently

    更新日期:2020-08-01
  • Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage
    bioRxiv. Biophys. Pub Date : 2020-07-30
    DANIEL FRANKEL; Ewan St John Smith; Kenneth Rankin; Nicolas Cenac; Matthew Davies; Janet Reiko Kumita; Michele Vendruscolo; Yavuz Kulaberoglu; Paulina Urriola Munoz; Justine Bertrand-michel; Melissa R Pergande; Swapan Preet; Thomas Park; Andrew Smith; Bharat Bhushan; Stephanie Cologna

    Naked mole-rats are extraordinarily long-lived rodents that do not develop age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta peptide, even from a young age Therefore, these animals offer an opportunity to investigate mechanisms of resistance against the neurotoxicity of amyloid beta aggregation

    更新日期:2020-07-31
  • Towards chemical accuracy for alchemical free energy calculations with hybrid physics-based machine learning / molecular mechanics potentials
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Dominic A. Rufa; Hannah E. Bruce Macdonald; Josh Fass; Marcus Wieder; Patrick B. Grinaway; Adrian E. Roitberg; Olexandr Isayev; John D. Chodera

    Alchemical free energy methods with molecular mechanics (MM) force fields are now widely used in the prioritization of small molecules for synthesis in structure-enabled drug discovery projects because of their ability to deliver 1-2 kcal/mol accuracy in well-behaved protein-ligand systems. Surpassing this accuracy limit would significantly reduce the number of compounds that must be synthesized to

    更新日期:2020-07-31
  • Unfolding of the chromatin fiber driven by overexpression of bridging factors
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Isha Malhotra; Bernardo Oyarzún; Bortolo Mognetti

    Nuclear molecules control the functional properties of the chromatin fiber by shaping its morphological properties. The biophysical mechanisms controlling how bridging molecules compactify the chromatin are a matter of debate. On the one side, bridging molecules could cross-link faraway sites and fold the fiber through the formation of loops. Interacting bridging molecules could also mediate long-range

    更新日期:2020-07-30
  • Single-Molecule Micromanipulation Studies Of Methylated DNA
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Tetiana Zaichuk; John Marko

    Cytosine methylated at the 5-carbon position is the most widely studied reversible DNA modification. Prior findings indicate that methylation can alter mechanical properties. However, those findings were qualitative and sometimes contradictory, leaving many aspects unclear. By applying single-molecule magnetic force spectroscopy techniques allowing for direct manipulation and dynamic observation of

    更新日期:2020-07-30
  • Control and mechanisms of pulsatile flows in epithelial monolayers
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Raghavan Thiagarajan; Alka Bhat; Guillaume Salbreux; Mandar M. Inamdar; Daniel Riveline

    Epithelial cells flows are observed both in vivo and in vitro and are essential for morphogenesis. Here, we show that pulsatile flows involving local contraction and expansion of a tissue can arise in vitro in an epithelial monolayer of Madine Darby Canine Kidney (MDCK) cells. The strength of pulsation can be modulated through friction heterogeneity by observing the monolayer dynamics on micro-contact

    更新日期:2020-07-30
  • High-Pressure NMR Reveals Volume and Compressibility Differences Between Two Stably Folded Protein Conformations
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Xingjian Xu; Donald Gagné; James M. Aramini; Kevin H. Gardner

    Proteins often interconvert between different conformations in ways critical to their function. However, manipulating the equilibrium positions and kinetics of such conformational transitions has been traditionally challenging. Pressure is an effective thermodynamic variable for favoring the population of high energy protein conformational states with smaller volumes, as elegantly demonstrated in its

    更新日期:2020-07-30
  • Viscoelastic properties of wheat gluten in a molecular dynamics study
    bioRxiv. Biophys. Pub Date : 2020-07-30
    Łukasz Mioduszewski; Marek Cieplak

    Wheat (Triticum spp.) gluten consists mainly of intrinsincally disordered storage proteins (glutenins and gliadins) that can form megadalton-sized networks. These networks are responsible for the unique viscoelastic properties of wheat dough and affect the quality of bread. These properties have not yet been studied by molecular level simulations. Here, we use a newly developed α-C-based coarse-grained

    更新日期:2020-07-30
  • Disease-Linked Super-Trafficking of a Mutant Potassium Channel
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Hui Huang; Laura M. Chamness; Carlos G. Vanoye; Georg Kuenze; Jens Meiler; Alfred L George; Jonathan P Schlebach; Charles Sanders

    Gain-of-function (GOF) mutations in the KCNQ1 voltage-gated potassium channel can induce cardiac arrhythmia. We tested whether any of the known GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface: super-trafficking. We found that levels of R231C KCNQ1 in the plasma membrane are 5-fold higher than wild type KCNQ1. This arises from both enhanced translocon-mediated

    更新日期:2020-07-30
  • Radiation-induced cell cycle perturbations: a computational tool validated with flow-cytometry data
    bioRxiv. Biophys. Pub Date : 2020-07-29
    LEONARDO LONATI; Sofia Barbieri; Isabella Guardamagna; Andrea Ottolenghi; Giorgio Baiocco

    Cell cycle progression can be studied with computational models that allow to describe and predict its perturbation by agents as ionizing radiation or drugs. Such models can then be integrated in tools for pre-clinical/clinical use, e.g. to optimize kinetically-based administration protocols of radiation therapy and chemotherapy. We present a deterministic compartmental model, specifically reproducing

    更新日期:2020-07-30
  • Generalizing HMMs to Continuous Time for Fast Kinetics: Hidden Markov Jump Processes
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Zeliha Kilic; Ioannis Sgouralis; Steve Presse

    The hidden Markov model (HMM) is a framework for time series analysis widely applied to single molecule experiments. It has traditionally been used to interpret signals generated by systems, such as single molecules, evolving in a discrete state space observed at discrete time levels dictated by the data acquisition rate. Within the HMM framework, originally developed for applications outside the Natural

    更新日期:2020-07-30
  • On the molecular mechanism of SARS-CoV-2 retention in the upper respiratory tract
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Kristina A Paris; Ulises Santiago; Carlos J. Camacho

    Cell surface receptor engagement is a critical aspect of viral infection. At low pH, binding of SARS-CoV and its ACE2 receptor has a tight interaction that catalyzes the fusion of the spike and endosomal membranes followed by genome release. Largely overlooked has been the role of neutral pH in the respiratory tract, where we find that SARS-CoV stabilizes a transition state that enhances the off-rate

    更新日期:2020-07-30
  • Allosteric inhibition of the SARS-CoV-2 main protease - insights from mass spectrometry-based assays
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Tarick J El-Baba; Corinne A Lutomski; Anastassia L Kantsadi; Tika R Malla; Tobias John; Victor Mikhailov; Jani R Bolla; Christopher J Schofield; Nicole Zitzmann; Ioannis Vakonakis; Carol V Robinson

    Following translation of the SARS-CoV-2 RNA genome into two viral polypeptides, the main protease Mpro cleaves at eleven sites to release non-structural proteins required for viral replication. MPro is an attractive target for antiviral therapies to combat the coronavirus-2019 disease (COVID-19). Here, we have used native mass spectrometry (MS) to characterize the functional unit of Mpro. Analysis

    更新日期:2020-07-30
  • Crystal structure reveals the full Ras:Raf interface and advances mechanistic understanding of Raf activation
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Trinity Cookis; Carla Mattos

    The interaction between Ras and Raf-kinase through the Ras-binding (RBD) and cysteine-rich domains (CRD) of Raf is essential for signaling through the mitogen-activated protein kinase (MAPK) pathway, yet the molecular mechanism leading to Raf activation has remained elusive. We present the 2.8 Å crystal structure of the HRas/CRaf-RBD_CRD complex showing the Ras/Raf interface as a continuous surface

    更新日期:2020-07-30
  • Long-range coupled motions underlie ligand recognition by a chemokine receptor
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Krishna Rajarathnam; Krishna Mohan Sepuru; Vinay Nair; Priyanka Prakash; Alemayehu Gorfe

    Chemokines are unusual class-A GPCR agonists because of their large size (~10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Whereas binding at Site-II triggers receptor activation, the role of Site-I is not known. Structures

    更新日期:2020-07-30
  • Cell-to-cell Mathematical Modeling of Arrhythmia Phenomena in the Heart
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Gabriel Lopez; Aurelio Nicolas; Graciela Roman; Rafael Godinez; Miguel Angel Castro

    With an aperiodic, self-similar distribution of two-dimensional arrangement of atrial cells, it is possible to simulate such phenomena as Fibrillation, Fluttering, and a sequence of Fibrillation-Fluttering. The topology of a network of cells may facilitate the initiation and development of arrhythmias such as Fluttering and Fibrillation. Using a GPU parallel architecture, two basic cell topologies

    更新日期:2020-07-30
  • Mind reading of the proteins: Deep-learning to forecast molecular dynamics
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Chitrak Gupta; John Kevin Cava; Daipayan Sarkar; Eric A Wilson; John Vant; Steven Murray; Abhishek Singharoy; Shubhra Kanti Karmaker

    Molecular dynamics (MD) simulations have emerged to become the back- bone of today's computational biophysics. Simulation tools such as, NAMD, AMBER and GROMACS have accumulated more than 100,000 users. Despite this remarkable success, now also bolstered by compatibility with graphics processor units (GPUs) and exascale computers, even the most scalable simulations cannot access biologically relevant

    更新日期:2020-07-30
  • UNCG RNA tetraloop as a formidable force-field challenge for MD simulations
    bioRxiv. Biophys. Pub Date : 2020-07-29
    Klaudia Mrazikova; Vojtech Mlynsky; Petra Kuhrova; Pavlina Pokorna; Holger Kruse; Miroslav Krepl; Michal Otyepka; Pavel Banas; Jiri Sponer

    Explicit solvent atomistic molecular dynamics (MD) simulations represent an established technique to study structural dynamics of RNA molecules and an important complement for diverse experimental methods. However, performance of molecular mechanical (MM) force fields (ffs) remains far from satisfactory even after decades of development, as apparent from a problematic structural description of some

    更新日期:2020-07-30
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