scholarly journals Scalable Analysis of Authentic Viral Envelopes on FRONTERA

2020 ◽  
Author(s):  
Fabio González-Arias ◽  
Tyler Reddy ◽  
John E. Stone ◽  
Jodi A. Hadden-Perilla ◽  
Juan R. Perilla
Keyword(s):  
Large Scale ◽  
Viral Envelope ◽  
Host Cells ◽  
Parallel Computer ◽  
Modeling And Analysis ◽  
Large Scale Analysis ◽  
Viral Envelopes ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Scalable Analysis

AbstractEnveloped viruses infect host cells via fusion of their viral envelope with the plasma membrane. Upon cell entry, viruses gain access to all the macromolecular machinery necessary to replicate, assemble, and bud their progeny from the infected cell. By employing molecular dynamics simulations to characterize the dynamical and chemical-physical properties of viral envelopes, researchers can gain insights into key determinants of viral infection and propagation. Here, the Frontera supercomputer is leveraged for large-scale analysis of authentic viral envelopes, whose lipid compositions are complex and realistic. VMD with support for MPI is employed on the massive parallel computer to overcome previous computational limitations and enable investigation into virus biology at an unprecedented scale. The modeling and analysis techniques applied to authentic viral envelopes at two levels of particle resolution are broadly applicable to the study of other viruses, including the novel coronavirus that causes COVID-19. A framework for carrying out scalable analysis of multi-million particle MD simulation trajectories on Frontera is presented, expanding the the utility of the machine in humanity’s ongoing fight against infectious disease.

scholarly journals Sendai virus recruits cellular villin to remodel actin cytoskeleton during fusion with hepatocytes

2017 ◽  
Vol 28 (26) ◽  
pp. 3801-3814 ◽  
Author(s):  
Sunandini Chandra ◽  
Raju Kalaivani ◽  
Manoj Kumar ◽  
Narayanaswamy Srinivasan ◽  
Debi P. Sarkar
Keyword(s):  
Membrane Fusion ◽  
Viral Entry ◽  
Sendai Virus ◽  
Viral Envelope ◽  
Bioactive Molecules ◽  
Host Cells ◽  
Actin Dynamics ◽  
Envelope Glycoproteins ◽  
Animal Cells ◽  
Viral Envelopes

Reconstituted Sendai viral envelopes (virosomes) are well recognized for their promising potential in membrane fusion–mediated delivery of bioactive molecules to liver cells. Despite the known function of viral envelope glycoproteins in catalyzing fusion with cellular membrane, the role of host cell proteins remains elusive. Here, we used two-dimensional differential in-gel electrophoresis to analyze hepatic cells in early response to virosome-induced membrane fusion. Quantitative mass spectrometry together with biochemical analysis revealed that villin, an actin-modifying protein, is differentially up-regulated and phosphorylated at threonine 206—an early molecular event during membrane fusion. We found that villin influences actin dynamics and that this influence, in turn, promotes membrane mixing through active participation of Sendai viral envelope glycoproteins. Modulation of villin in host cells also resulted in a discernible effect on the entry and egress of progeny Sendai virus. Taken together, these results suggest a novel mechanism of regulated viral entry in animal cells mediated by host factor villin.

scholarly journals How Does the Novel Coronavirus Interact with the Human ACE2 Enzyme? A Thermodynamic Answer

2020 ◽  
Author(s):  
Jones de Andrade ◽  
Paulo Fernando Bruno Gonçalves ◽  
Paulo Augusto Netz
Keyword(s):  
Free Energy ◽  
Protein Complexes ◽  
Minimum Free Energy ◽  
New Drugs ◽  
Host Cells ◽  
Spike Protein ◽  
Health Concern ◽  
Novel Coronavirus ◽  
Dynamics Simulations ◽  
Free Energy Of Binding

<p>The SARS-CoV-2 coronavirus pandemic is certainly the most important public health concern today. Until now there are no vaccines or treatments available, despite intensive international efforts. One of the targets for new drugs is the Coronavirus Spike Protein, responsible for its binding and entry into the host cells. The Receptor Binding Domain (RBD) found at the Spike Protein recognizes the human angiotensin-converting enzyme 2 (hACE2). The present in silico study discuss structural and thermodynamic aspects of the protein complexes involving the RBD’s from the 2002 SARS-CoV and 2019 SARS-CoV-2 with the hACE2. Molecular docking and molecular dynamics simulations of the complexes and isolated proteins were performed, providing insights on their detailed pattern of interactions, and estimating the free energy of binding. The obtained results support previous studies indicating that the chemical affinity of the new SARS-CoV-2 for the hACE2 enzyme virus is much higher than the 2002 SARS-CoV. The herein calculated Gibbs free energy of binding to the hACE2 enzyme is, depending on the technique, from 5.11 kcal/mol to 8.39 kcal/mol more negative in the case of the new coronavirus’ RBD. In addition, within each employed technique, this free energy is consistently 61±2% stronger for SARS-CoV-2 than for SARS-CoV. This work presents a chemical reason for the difficulty in treating the SARS-CoV-2 virus using drugs targeting its Spike Protein, as well as helps to explain its infectivity, while defining a minimum free energy of binding for new drugs to be designed against this disease.<br></p>

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

2020 ◽  
Author(s):  
Aditya Padhi ◽  
Aniruddha Seal ◽  
Timir Tripathi
Keyword(s):  
Molecular Dynamics ◽  
Global Economy ◽  
Md Simulation ◽  
Treatment Guidelines ◽  
Host Cells ◽  
Virus Binding ◽  
Drug Candidates ◽  
Fusion Inhibition ◽  
Novel Coronavirus ◽  
Dynamics Simulations

<p>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 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 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.</p>

scholarly journals Simple Resazurin-Based Microplate Assay for Measuring Chlamydia Infections

2013 ◽  
Vol 57 (6) ◽  
pp. 2838-2840 ◽  
Author(s):  
Ichie Osaka ◽  
P. Scott Hefty
Keyword(s):  
Large Scale ◽  
Host Cells ◽  
Scale Analysis ◽  
Content Type ◽  
Large Scale Analysis ◽  
Resazurin Assay ◽  
Inhibitory Compound ◽  
Microscopy Method ◽  
Conventional Microscopy ◽  
Time Required

ABSTRACTThe conventional method for quantification ofChlamydiainfection using fluorescence microscopy typically involves time- and labor-intensive manual enumeration, which is not applicable for a large-scale analysis required for an inhibitory compound screen. In this study, an alamarBlue (resazurin) assay was adopted to measureChlamydiainfection by measuring the redox capability of infected host cells in a 96-well format. The assay provided measurements comparable to those of the conventional microscopy method while drastically reducing the time required for analysis.

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

2020 ◽  
Author(s):  
Aditya Padhi ◽  
Aniruddha Seal ◽  
Timir Tripathi
Keyword(s):  
Molecular Dynamics ◽  
Global Economy ◽  
Md Simulation ◽  
Treatment Guidelines ◽  
Host Cells ◽  
Virus Binding ◽  
Drug Candidates ◽  
Fusion Inhibition ◽  
Novel Coronavirus ◽  
Dynamics Simulations

<p>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 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 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.</p>

scholarly journals Infectivity of dengue virus serotypes 1 and 2 is correlated to E protein intrinsic dynamics but not to envelope conformations

2018 ◽  
Author(s):  
Kamal Kant SHARMA ◽  
Xin-Xiang LIM ◽  
Sarala Neomi TANTIRIMUDALIGE ◽  
Anjali Gupta ◽  
Jan K MARZINEK ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Conformational Changes ◽  
Large Scale ◽  
Morphological Changes ◽  
Divalent Cations ◽  
Virulent Strain ◽  
Viral Envelope ◽  
Temperature Dependent ◽  
Dengue Virus Serotypes ◽  
Dynamics Simulations

Dengue is a mosquito-borne virus with dire health and economic impact. Dengue is responsible for an estimated ~390 million infections per year, with Dengue 2 (DENV2) being the most virulent strain among the four serotypes. Interestingly, it is also for strains of this serotype that temperature-dependent large scale morphological changes, termed as 'breathing', have been observed. Although, the structure of these morphologies has been solved to 3.5 Angstrom resolution, the dynamics of the viral envelope are unknown. Here, we combine fluorescence and mass spectrometry and molecular dynamics simulations to provide insights into DENV2 structural dynamics in comparison to DENV1. We observe hitherto unseen conformational changes and structural dynamics of the DENV2 envelope that are influenced by both temperature and divalent cations. Our results show that for DENV2 and DENV1 the intrinsic dynamics but not the specific morphologies are correlated to viral infectivity.

Massively Parallel Molecular Dynamics Simulations of Two-dimensional Materials at High Strain Rates

1992 ◽  
Vol 291 ◽  
Author(s):  
Norman J. Wagner ◽  
Brad Lee Holian
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Spall Strength ◽  
Computer Experiments ◽  
Dislocation Dynamics ◽  
Parallel Computer ◽  
Massively Parallel ◽  
Connection Machine ◽  
Dynamics Simulations

ABSTRACTLarge scale molecular dynamics simulations on a massively parallel computer are performed to investigate the mechanical behavior of 2-dimensional materials. A model embedded atom many- body potential is examined, corresponding to “ductile” materials. A parallel MD algorithm is developed to exploit the architecture of the Connection Machine, enabling simulations of > 106atoms. A model spallation experiment is performed on a 2-D triagonal crystal with a well-defined nanocrystalline defect on the spall plane. The process of spallation is modelled as a uniform adiabatic expansion. The spall strength is shown to be proportional to the logarithm of the applied strain rate and a dislocation dynamics model is used to explain the results. Good predictions for the onset of spallation in the computer experiments is found from the simple model. The nanocrystal defect affects the propagation of the shock front and failure is enhanced along the grain boundary.

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