Corpus overview


Overview

MeSH Disease

Human Phenotype

Rigidity (10)

Falls (1)


Transmission

Seroprevalence

antibody (1)

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    Flexibility and mobility of SARS-CoV-2-related protein structures

    Authors: Rudolf A Roemer; Navodya Sophie Roemer; Anne Katrine Wallis

    doi:10.1101/2020.07.12.199364 Date: 2020-07-12 Source: bioRxiv

    The worldwide CoVid-19 pandemic has led to an unprecedented push across the whole of the scientific community to develop a potent antiviral drug and vaccine as soon as possible. Existing academic, governmental and industrial institutions and companies have engaged in large-scale screening of existing drugs, in vitro, in vivo and in silico. Here, we are using in silico modelling of SARS-CoV-2 drug targets, i.e. SARS-CoV-2 protein structures as deposited on the Protein Databank (PDB). We study their flexibility, rigidity HP and mobility, an important first step in trying to ascertain their dynamics for further drug-related docking studies. We are using a recent protein flexibility modelling approach, combining protein structural rigidity HP with possible motion consistent with chemical bonds and sterics. For example, for the SARS-CoV-2 spike protein in the open configuration, our method identifies a possible further opening and closing of the S1 subunit through movement of SB domain. With full structural information of this process available, docking studies with possible drug structures are then possible in silico. In our study, we present full results for the more than 200 thus far published SARS-CoV-2-related protein structures in the PDB.

    Spike protein fusion loop controls SARS-CoV-2 fusogenicity and infectivity

    Authors: Debnath Pal

    doi:10.1101/2020.07.07.191973 Date: 2020-07-07 Source: bioRxiv

    The Spike is a hallmark coronavirus protein that determines virus fusion, entry and spread in the host, and thus holds clues for the rapid spread of the SARS-CoV-2 pandemic. We have investigated the Spike from six β-coronaviruses, including the SARS-CoV-2, and find that their surface-exposed fusion peptides constituting the fusion loop are spatially organized contiguous to each other to work synergistically for triggering the virus-host membrane fusion process. The SARS-CoV-2 fusion peptides have unique physicochemical properties, accrued in part from the presence of consecutive prolines that impart backbone rigidity HP which aids the virus fusogenicity. The specific contribution of these prolines has been inferred from comparative studies of their deletion mutant in a fellow murine β-coronavirus MHV-A59 that show significantly diminished fusogenicity in vitro and associated pathogenesis in vivo. The Spike cleavage-linked priming and fusogenic conformational transition steered by the fusion loop may be critical for the SARS-CoV-2 spread.Summary The Spike protein on the SARS-CoV-2 surface is the prime mediator of COVID-191 because of its central role in virus-host attachment, virus-entry, and virus-spread2. The contagious nature of SARS-CoV-2 infection MESHD has been attributed to dense glycosylation of the Spike glycoprotein3, its high affinity of binding to human ACE2 receptor4, and cleavage5. While these may be imperative, it does not explain the uncontrolled infectivity. Here we show that properties of the fusion peptides constituting the fusion loop of SARS-CoV-2 Spike that triggers the virus fusion, distinguishes it from the other five β-coronaviruses. The SARS-CoV-2 Spike trimer surface is relatively more hydrophobic, including the surface contributed by the fusion peptides. The fusion peptides are structurally rigid owing to its consecutive prolines, aromatic/hydrophobic clusters, a stretch of consecutive β-branched amino acids, and the hydrogen bonds. The role of rigidity HP accrued from the presence of consecutive prolines contributing to virus fusogenicity can be deciphered from our previous murine β-coronavirus, MHV-A59 studies6. The synergy brought about by the global location of the surface exposed fusion peptides, their physicochemical features, and the fusogenic conformational transition appears to drive the fusion process, which may explain the severity of the infection MESHD and widespread nature of the COVID-19 pandemic.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Map of SARS-CoV-2 spike epitopes not shielded by glycans.

    Authors: Mateusz Sikora; Sören von Bülow; Florian E. C. Blanc; Michael Gecht; Roberto Covino; Gerhard Hummer

    doi:10.1101/2020.07.03.186825 Date: 2020-07-03 Source: bioRxiv

    The severity of the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, calls for the urgent development of a vaccine. The primary immunological target is the SARS-CoV-2 spike (S) protein. S is exposed on the viral surface to mediate viral entry into the host cell. To identify possible antibody SERO binding sites not shielded by glycans, we performed multi-microsecond molecular dynamics simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins. By mapping steric accessibility, structural rigidity HP, sequence conservation and generic antibody SERO binding signatures, we recover known epitopes on S and reveal promising epitope candidates for vaccine development. We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures, highlighting the importance of structural dynamics in epitope mapping.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Decoding asymptomatic TRANS COVID-19 infection MESHD and transmission TRANS

    Authors: Rui Wang; Yuta Hozumi; Changchuan Yin; Guo-Wei Wei

    id:2007.01344v1 Date: 2020-07-02 Source: arXiv

    Coronavirus disease MESHD 2019 (COVID-19) is a continuously devastating public health and the world economy. One of the major challenges in controlling the COVID-19 outbreak is its asymptomatic infection MESHD asymptomatic TRANS and transmission TRANS, which are elusive and defenseless in most situations. The pathogenicity and virulence of asymptomatic TRANS COVID-19 remain mysterious. Based on the genotyping of 20656 Severe Acute Respiratory Syndrome MESHD Coronavirus 2 (SARS-CoV-2) genome isolates, we reveal that asymptomatic infection MESHD asymptomatic TRANS is linked to SARS-CoV-2 11083G>T mutation, i.e., leucine (L) to phenylalanine (F) substitution at the residue 37 (L37F) of nonstructure protein 6 (NSP6). By analyzing the distribution of 11083G>T in various countries, we unveil that 11083G>T may correlate with the hypotoxicity of SARS-CoV-2. Moreover, we show a global decaying tendency of the 11083G>T mutation ratio indicating that 11083G>T hinders SARS-CoV-2 transmission TRANS capacity. Sequence alignment found both NSP6 and residue 37 neighborhoods are relatively conservative over a few coronaviral species, indicating their importance in regulating host cell autophagy to undermine innate cellular defense against viral infection MESHD. Using machine learning and topological data analysis, we demonstrate that mutation L37F has made NSP6 energetically less stable. The rigidity HP and flexibility index and several network models suggest that mutation L37F may have compromised the NSP6 function, leading to a relatively weak SARS-CoV subtype. This assessment is a good agreement with our genotyping of SARS-CoV-2 evolution and transmission TRANS across various countries and regions over the past few months.

    Shell Disorder Analysis Suggests That Pangolins Offered a Window for a Silent Spread of an Attenuated SARS-CoV-2 Precursor among Humans

    Authors: Gerard Kian-Meng Goh; A. Keith Dunker; James A. Foster; Vladimir N. Uversky

    id:202006.0327/v1 Date: 2020-06-28 Source: Preprints.org

    A model to predict the relative levels of respiratory and fecal-oral transmission TRANS potentials of coronaviruses (CoVs) by measuring the percentage of protein intrinsic disorder (PID) of the M (Membrane) and N (nucleoprotein) proteins in their outer and inner shells, respectively, was built before the MERS-CoV outbreak. Application of this model to the 2003 SARS-CoV indicated that this virus with MPID = 8.6% and NPID = 50.2% falls HP into group B, which consists of CoVs with intermediate levels of both fecal-oral and respiratory transmission TRANS potentials. Further validation of the model came with MERS-CoV (MPID = 9%, NPID = 44%) and SARS-CoV-2 (MPID = 5.5%, NPID = 48%) falling HP into the groups C and B, respectively. Group C contains CoVs with higher fecal-oral but lower respiratory transmission TRANS potentials. Unlike SARS-CoV, SARS-CoV-2 with MPID = 5.5% has one of the hardest outer shells among CoVs. This shell hardness is believed to be responsible for high viral loads in the mucus and saliva making it more contagious than SARS-CoV. The hard shell is able to resist the anti-microbial enzymes in body fluids. Further searches have found that high rigidity HP of outer shell is characteristic for the CoVs of burrowing animals, such as rabbits (MPID = 5.6%) and pangolins (MPID = 5-6%), which are in contact with the buried feces. A closer inspection of pangolin-CoVs from 2017-19 reveals that these animals provided a unique window of opportunity for the entry of an attenuated SARS-CoV-2 precursor into the human population in 2017 or earlier, with the subsequent slow and silent spread as a mild cold that followed by its mutations into the current more virulent form. Evidence of this lies in the similarity of shell disorder and genetic proximity of the pangolin-CoVs to SARS-CoV-2 (~90%). A 2017 pangolin-CoV strain shows evidence of higher levels of attenuation and higher fecal-oral transmission TRANS associated with lower human infectivity via having lower NPID (44.8%). Our shell disorder analysis also revealed that lower inner shell disorder is associated with the lesser virulence in a variety of viruses.

    How Does Arbidol Inhibit the Novel Coronavirus SARS-CoV-2? Atomistic Insights from Molecular Dynamics Simulations

    Authors: Aditya Padhi; Aniruddha Seal; Timir Tripathi

    doi:10.26434/chemrxiv.12464576.v1 Date: 2020-06-15 Source: ChemRxiv

    The COVID-19 pandemic is spreading at an alarming rate, posing an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered for severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) treatment. China's prevention and treatment guidelines suggest the use of an anti-influenza drug, Arbidol, for the clinical treatment of COVID-19. Reports indicate that Arbidol could neutralize the SARS-CoV-2. Monotherapy with Arbidol is found superior to Lopinavir-Ritonavir or Favipiravir in the treatment of COVID-19. In the SARS-CoV-2, Arbidol acts upon interfering in virus binding to host cells. However, the detailed understanding of Arbidol induced inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the Arbidol-induced SARS-CoV-2 membrane fusion inhibition and propose a model of inhibition. Molecular dynamics (MD) simulation-based analyses demonstrate that Arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between RBD and ACE2 in the Arbidol-bound RBD/ACE2 complex, suggesting that Arbidol could generate favorable interactions between them. Based on our MD simulation results, we propose that the binding of Arbidol induced structural rigidity HP in the virus glycoprotein resulting in restriction of the conformational rearrangements associated with membrane attachment and virus entry.Further, key residues of RBD and ACE2 that interacted with Arbidol were identified, opening the doors for the development of therapeutic strategies and higher efficacy Arbidol derivatives or lead drug candidates.

    Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: an in silico investigation

    Authors: Olivier Sheik Amamuddy; Gennady M Verkhivker; Ozlem Tastan Bishop

    doi:10.1101/2020.05.29.123190 Date: 2020-06-01 Source: bioRxiv

    The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mpro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. Domains from each Mpro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants. A mirrored interprotomer pocket was found to be correlated to the catalytic site using compaction dynamics, and can be a potential allosteric target. The high number of titratable amino acids of Mpro may indicate an important role of pH on enzyme dynamics, as previously reported for SARS-CoV. Independent coarse-grained Monte Carlo simulations suggest a link between rigidity HP/mutability and enzymatic function.

    The impact of COVID-19 on the UK fresh food supply chain

    Authors: Rebecca Mitchell; Roger Maull; Simon Pearson; Steve Brewer; Martin Collison

    id:2006.00279v1 Date: 2020-05-30 Source: arXiv

    The resilience of the food supply chain is a matter of critical importance, both for national security and broader societal well bring. COVID19 has presented a test to the current system, as well as means by which to explore whether the UK's food supply chain will be resilient to future disruptions. In the face of a growing need to ensure that food supply is more environmentally sustainable and socially just, COVOD19 also represents an opportunity to consider the ability of the system to innovative, and its capacity for change. The purpose of this case based study is to explore the response and resilience of the UK fruit and vegetable food supply chain to COVID19, and to assess this empirical evidence in the context of a resilience framework based on the adaptive cycle. To achieve this we reviewed secondary data associated with changes to retail demand, conducted interviews with 23 organisations associated with supply to this market, and conducted four video workshops with 80 organisations representing half of the UK fresh produce community. The results highlight that, despite significant disruption, the retail dominated fresh food supply chain has demonstrated a high degree of resilience. In the context of the adaptive cycle, the system has shown signs of being stuck in a rigidity HP trap, as yet unable to exploit more radical innovations that may also assist in addressing other drivers for change. This has highlighted the significant role that innovation and R&D communities will need to play in enabling the supply chain to imagine and implement alternative future states post COVID.

    Social Distancing as a Network Population Game in a Socially Connected World

    Authors: Zhijun Wu

    id:2005.12506v1 Date: 2020-05-26 Source: arXiv

    While social living is considered to be an indispensable part of human life in today's ever-connected world, social distancing has recently received much public attention on its importance since the outbreak of the coronavirus pandemic. In fact, social distancing has long been practiced in nature among solitary species, and been taken by human as an effective way of stopping or slowing down the spread of infectious diseases MESHD. Here we consider a social distancing problem for how a population, when in a world with a network of social sites, such as schools, restaurants, shopping centers, residential areas, etc., decides to visit or stay at some sites while avoiding or closing down others so that the social contacts across the network can be minimized. We model this problem as a network population game, where every individual tries to find some network sites to visit or stay so that he/she can minimize all his/her contacts. In the end, an optimal strategy can be found for every one, when the resulting distribution of the population over the network reaches an equilibrium. We show that a large class of equilibrium strategies can be obtained by selecting a set of network sites that forms a so-called maximal r-regular subnetwork. The latter includes many well studied network types, such as the maximal independent set (r=0), the maximal strong matching (r=1), the maximal set of independent cycles (r=2), etc. They are easy to identify or construct, and can be completely disconnected (with r = 0) for the most strict isolation, or allow certain degree of connectivities (with r > 0) for more flexible distancing. We derive the equilibrium conditions of these strategies, and analyze their rigidity HP and flexibility on different types of r-regular subnetworks. We provide an overview on algorithms that can be used for computing maximal r-regular subnetworks and their associated distancing strategies.

    Is the Rigidity HP of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? An Answer from All-Atoms Simulations

    Authors: Angelo Spinello; Andrea Saltalamacchia; Alessandra Magistrato

    doi:10.26434/chemrxiv.12091260.v3 Date: 2020-04-22 Source: ChemRxiv

    The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.

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MeSH Disease
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