PRACE support to mitigate impact of COVID-19 pandemic: Awarded Projects

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The Gordon Bell Special Prize for High Performance Computing-Based COVID-19 Research is accepting nominations for 2020 and 2021 awards to to recognize outstanding research achievement towards the understanding of the COVID-19 pandemic through the use of high-performance computing (HPC). Click on the button below to find out more.

Awarded Projects

Project Title: COVID-HP

Project Leader: Prof. Jean-Philip Piquemal, Sorbonne Université, France

Resource Awarded

  • 20 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Biomolecular research to understand the mechanisms of the virus infection/Bio-simulations to develop therapeutics

Abstract
In the face of the growing pandemic caused by the retrovirus SARS-CoV-2 (Covid-19), there is an urgent need for inhibitors capable of selectively targeting some of its key proteins, but perhaps also key nucleic acid sequences in its genome. This project, which brings together a consortium of complementary teams, is based on several strengths:

  1. The recent provision of high-resolution structures of several Covid-19 proteins
  2. The availability of a new polarized molecular dynamics software, Tinker-HP, to achieve simulation quality that cannot be achieved with other software
  3. The ability to reprocess Tinker-HP trajectories through a set of screening and docking software to test new molecules active against Covid-19.

Article on this project: Attacking COVID-19 from every angle

Project Title: A computational study of the reactivity in the main protease of SARS-CoV-2 to guide the design of inhibitors

Project Leader: Prof. Iñaki Tuñón, Universidad de Valencia, Spain

Resource Awarded

  • 23 000 000 core hours on MareNostrum 4 x86, hosted by BSC, Spain
  • 23 000 000 core hours on MareNostrum 4 P9/V100, hosted by BSC, Spain

Project Duration: 2.5 months

Research Field: Computational Chemistry

Abstract
In this work we analyze the binding of the substrate and the reaction mechanisms for the main protease of SARS-CoV-2, also referred to as 3C-like protease (3CLpro). This enzyme plays an essential role during the replication of the virus and has not closely related homologues in human beings, making it an attractive drug target. The 3CLpro exists as a functional homodimer with two active sites in charge of cleaving the translated polyproteins into individual fragments to be used by the coronavirus. As other cysteine proteases each of the active sites contains a Cys-His catalytic dyad in charge of the hydrolysis of the peptide bond at specific sites of a polypeptide chain. Several structures of this protease have been already resolved by means of x-ray crystallography and deposited in the Protein Data Bank (PDB), including the free protease, PDB codes 6Y2E and 6Y84, and inhibitor bound protease, PDB codes 6LU7 and 6Y2F. The SARS-CoV-2 main protease has a structure virtually identical to the orthologue from SRAS-CoV (96% identity). Not only that, residues involved in catalysis, binding and dimerization processes are fully conserved and the target polyprotein sequences also show a large degree of identity. In this work we take benefit of these similarities and the existence of ligand-bound structures to build a structural model of a peptide substrate-enzyme Michaelis complex for the computational study of the chemical reaction catalyzed by this enzyme.

Project Title: Characterisation of a peptide network with a combined antiviral and antiinflammatory activity against COVID-19

Project Leader: Dr Hansel Gómez Martínez, NURITAS Ltd., Ireland

Resource Awarded

  • 40 000 000 core hours on Piz Daint hosted by CSCS, Switzerland

Project Duration: 6 months

Research Field: Drug discovery / Molecular Modelling

Abstract

Our company is also committed to contribute to the mitigation of the COVID-19 pandemic. In that regard, we are willing to find bioactive peptides binding to as many targets as possible in the SARSCoV-2-Human Protein interactome. We have identified already 6 targets from the virus with experimental structures available: SARS-CoV-2 Spike protein, main protease, nucleocapsid protein, NSP3, NSP10 and NSP15, and we will extend that list as more structures become available or homology modeling is feasible. In fact, the 30kb genome of SARS-CoV-2 encodes as many as 16 non-structural proteins (Nsp1-16) which form the replicase/transcriptase complex (RTC) as well as four structural proteins: Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N)17, and nine putative accessory factors. Moreover, in a more recent study , providing the more exhaustive description so far to the SARS-CoV-2-Human Protein-Protein Interaction Map, the authors used affinity purification mass spectrometry (AP-MS) to identify 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs), including 66 druggable human proteins.

The expected outcome is to find a cocktail of natural peptides, unlocked from natural sources and exhibiting anti-viral properties against SARS-CoV-2. Moreover, since similar coronaviruses use comparable infection mechanisms, these peptides could, in principle, provide some universal protection against other viruses of the same family. Finally, Nuritas has being extensively working on other bioactivity profiles like anti-inflammation peptides for which we have already candidates in preclinical assays. Modulating inflammation is relevant in any infectious process, including COVID-19 and therefore we could include these peptides to alleviate symptoms, like inflammation, which are tightly associated to the pneumonia and eventual mortality of patients. The impact of providing a cocktail of natural peptides exhibiting both anti-viral and anti-inflammatory activity would be a remarkable and relatively cheap solution contributing to mitigate the disease.

Project Title: COVID19: Computational screening and improvement of viral protein inhibitors

Project Leader: Prof. Dr Gerrit Groenhof, University of Jyväskylä, Finland

Resource Awarded

  • 15 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Chemistry, Structural biology, Molecular Dynamics

Abstract

From MD trajectories of docked spike protein-aptamer complexes (we have two already), we map out the contribution of individual nucleotides to the overall binding affinity via an energy decomposition analysis. Nucleotides with a significant contribution are systematically varied and the effect on the affinity is computed by means of so-called thermodynamic integration, which can provide accurate estimates for the effect of the nucleotide alteration on the binding free energy. Workflows developed within the contexts of the Academy of Finland FluProCad key-project and the European Union Bioexcel Center of Excellence (www.bioexcel.eu), are essential to scan these variations efficiently on High Performance Computing (tier 0 or 1) resources. In addition, we use the same simulation protocols to investigate whether chemical modification of the aptamers can improve their affinity and specificity for the viral spike protein.

In a parallel project we work together locally with Petri Pihko, who is an expert in organic synthesis, and Varpu Marjomäki, a virology specialist, on inhibition of the RdRp with nucleotide analogues. The Covid-19 RdRp structure was recently resolved to 2.9 A resolution with cryo-EM (6m71.pdb) and kindly shared with us by the authors. Since then, we already performed MD simulations of the RdRp complexed with double stranded RNA consisting of the template and primer. Next, we will perform free energy computations to predict the effects of chemical modification of nucleotide bases, both inside the nucleotide binding site before the polymerization reaction, as well as after insertion of the nucleotide into the RNA primer. We also want to investigate possible cooperative effects of the inhibitor by including multiple inhibitor bases into the primer strand, as these are speculated to induce conformational changes in the complex that ultimately can cause its arrest.

If successful, we anticipate novel post-infection therapeutics to slow down the COVID-19 outbreak until a suitable vaccine is available. Moreover, the developed drug design workflows and protocols will be readily available at possible future outbreaks of other infections.

Via github.com/bioexcel we will make all models, topologies etc. immediately available so that colleagues can scrutinize our results or use them for their own work. As we would be very happy to collaborate, we give permission to share our proposal with other applicants to speed up the formation of new collaboration networks.

Project Title: Characterization of SARS-CoV-2 envelope small membrane protein (E)

Project Leader: Prof. Matteo Dal Peraro, École Polytechnique Fédérale de Lausanne, Switzerland

Resource Awarded

  • 10 000 000 core hours on Piz Daint hosted by CSCS, Switzerland

Project Duration: 6 months

Research Field: Molecular simulation of biomolecules

Abstract

We will perform atomistic molecular dynamics (MD) simulations to characterize CoV2 E in its specific membrane environments and will study its properties as ion channel. Furthermore, as many viral proteins, CoV2 E is reported to be S-acylated at Cys40, Cys43 and Cys44 (12). The position of these adjacent acylation sites at the putative membrane-protein interface can be relevant for conferring enhanced stability to CoV2 E when embedded in the membrane, contributing to CoV2 much increased virulence. We will benefit from the active collaboration with the van der Goot lab at the EPFL (13) to investigate the implications of different S-acylation states on the structural and dynamic properties of CoV2 E.

The concrete output of this simulation campaign will be the characterization of CoV2 E in physiological states relevant for the viral life cycle. Once made available to the community, this dataset can be the foundation for (i) structure-based drug development and drugs repurposing campaigns for discovering CoV2 antivirals. Moreover, (ii) these models will enable the possibility to explore and rationalize the molecular mechanisms of viral infection implicated with CoV2 E. For instance, the interaction with other CoV2 structural proteins (e.g., interaction with membrane protein (M) is key for virus-like particles production and release, where E is required to maintain the spherical morphology of virions) and host proteins (e.g., Bcl-xL, PALS1 and syntenin)(10) can be studied to better clarify the mechanisms of CoV2 infection. CoV2 E, while critical for the viral life cycle, is still poorly explored: this study will contribute to foster and converge research lines on CoV2 E, with the final aim of developing new and effective antiviral strategies against COVID-19.

Interview with Project Leader.

 

Project Title: Polypharmacology-based antiviral design

Project Leader:Mr. Daniel Soler, Nostrum Biodiscovery (NBD), Spain

Resource Awarded

  • 4 000 000 core hours on SuperMUC-NG hosted by GCS at LRZ, Germany

Project Duration: 6 months

Research Field: Life Science

Abstract
We have devised a polypharmacology-based approach for addressing compound with activity among several COVID-19, SARS and MERS strains. Using a procedure which combines virtual screening and experimental assays we expect to obtain a promising hit molecule targeting several virus strains.

Project Title: Drug design on the 3CL-pro (Mpro) target protein of SARS-CoV2 using fast switching massively parallel alchemical approaches for absolute binding free energy determination

Project Leader:Prof. Piero Procacci, University of Florence, Italy

Resource Awarded

  • 20 000 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Bio-simulations to develop therapeutics and/or vaccines

Abstract
We aim at the in silico design of inhibitors (Small molecule compounds, SMC) of the 3CL-pro main protease of the SARS-CoV2. 3CL-pro cleaves the virus poliprotein pp1a, producing various functional virus proteins including RdPr (nsp12), which play a fundamental role in the transcription/replication during the infection. Hence blocking the 3CL-pro enzyme using a synthetic inhibitor can block the progression of Covid19. To this end we will use the so-called NS (nonequilibrium switching) alchemical approach in the context of explicit solvent atomistic simulations using state-of-the-art force fields (Amber99sb-ildn or OPLS-AA).

Project Title: Molecular Dynamics investigation of the interaction between ACE2 and the spike glycoprotein of SARS-CoV-2, in comparison with its predecessors from bat and pangolin

Project Leader:Prof. Giovanni Chillemi, University of Tuscia and CNR, Italy

Resource Awarded

  • 3 000 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Bio-simulations to develop therapeutics and/or vaccines

Abstract
Aim of this project is the comparison of structural and dynamic properties of the spyke glycoprotein in SARS-CoV-2, bat-SL-CoVs, BetaCoV_pangolin and the Italian variant hCoV-19/Italy/INMI1-isl/2020 by means of micro-second MD simulations. From these trajectories we can expect to shed light on some of the gained specific features that have facilitated the successful spread of the virus as compared to its predecessors. These results are preparatory for the identification of inhibitors that may reduce substantially pre-fusion conformation and therefore the infectivity of SARS-CoV-2. Particular attention will be paid toward the role played by six amino acid positions within the S1 subunit under positive/diversifying selection, likely involved in the adaptation to new host environments, i.e. positions 32 (S32F), 50 (L50S), 483 (Q483V), and 519 (N519H). Note that the original aminoacids are conserved in both bat and pangolin related virus (Tagliamonte et al., 2020).

Project Title: CardioVascular-COVID

Project Leader:Dr. Jazmín Aguado Sierra, Barcelona Supercomputing Center, Spain

Resource Awarded

  • 7 800 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Biomechanics

Abstract
As the crisis developed, the cardiovascular mechanics researchers in tight collaboration with Medical Doctors started applying Alya to two main problems that require the quick generation of evidence and information towards their use by clinicians:

  • Antimalarial and Antibiotic cardiotoxicity study: We aim to study the effect of antimalarial drugs on various human hearts with a variety of comorbidities that may be present in the infected population.
  • Venous-Arterial Extracorporeal membrane oxygenation therapy and the North-South Syndrome on patients with profound respiratory failure: The objective of this proposal is to use computational fluid dynamics (CFD) to better understand the complex hemodynamics associated with Nord-South Syndrome.

The impact of this research on the current COVID-19 pandemic will help to improve treatment of those affected most severely by the disease, ultimately reducing disease mortality.

Project Title: Targeting the interface of the COVID-19 spike protein with the ACE2 receptor

Project Leader:Prof. Francesco Luigi Gervasio, University College London, United Kingdom

Resource Awarded

  • 30 000 000 core hours on Hawk hosted by GCS at HLRS, Germany

Project Duration: 6 months

Research Field: Computational Physics/Chemistry

Abstract
In this project we will rationally design peptides and peptide-polymer conjugates targeting the S-ACE2 interface. We will target the interface from both sides (spike and ACE2) and directly validate the models. We will design a set of minimal peptides sequences that retain the general fold of ACE2’s helices at the interface while enhancing the binding affinity. Three different designs will be considered: a single helix, a helix-turn-helix or a helix-turn-helix-turn-helix. All of them will interact with the three spike residues essential for virulence F487, Q483, N501.

Project Title: Targeting conformational changes implicated in early events of viral entry

Project Leader: Prof. Francisco Javier Luque, University of Barcelona, Spain

Resource Awarded

  • 15 300 000 core hours on Hawk hosted by GCS at HLRS, Germany

Project Duration: 6 months

Research Field: Biomedicine – Computational Biology

Abstract
This project pursues a twofold aim: i) to disrupt viral entry by finding small molecules able to interfere with the conformational changes in the spike protein prior to binding to the host cell, and ii) to characterize the structural and energetic changes implicated in such conformational transition in both free and ligand-bound spike proteins.

Project Title: Identification of inhibitors of SARS-CoV-2 S protein

Project Leader: Dr. Sonsoles Martín-Santamaría, Spanish Research Council (CIB-CSIC), Spain

Resource Awarded

  • 25 000 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Drug repurposing, virtual screening, molecular simulations, peptide design

Abstract
We here propose the finding of possible small molecules by VS and computational design of peptides able to inhibit the S protein-mediated fusion mechanism by two main mechanisms: i) targeting the protein-protein interface among the monomers forming the S protein trimer, ii) inhibiting the S protein-ACE2 protein-protein interaction.

Priority will be given to the generic drug library (drug repurposing) since, in the event of finding promising inhibitory activity, they could follow a faster and more direct way through clinical trials. Other libraries will be screened: IQM antiviral library (collaboration) and others that we already have ready to be screened (ZINC, Molport, SPECS, fragment data bases).

Project Title: COVIDYN

Project Leader: Dr Himanshu Khandelia, University of Southern Denmark, Denmark

Resource Awarded

  • 35 000 000 core hours on Piz Daint hosted by CSCS, Switzerland

Project Duration: 6 months

Research Field: Molecular Dynamics Simulations, Computational Biophysics

Abstract
In this project, we will employ molecular dynamics (MD) simulations and Markov State Models of the ectodomain of the trimeric S protein to (1) provide molecular and kinetic insights into how the conformational equilibrium between the up and down conformations of the RBDs differs in SARS-Cov and SARS-Cov-2 (2) identify the molecular hotspots on the S protein which confer flexibility to the RBDs, and devise strategies to confine the RBD conformations to the down state.

Project Title: Epitope vaccines based on the dynamics of mutated SARS-CoV-2 proteins at all atom resolution

Project Leader: Prof. Evangelos Daskalakis, Cyprus University of Technology, Cyprus

Resource Awarded

  • 16 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Computational Biophysics, Bioinformatics

Abstract
Objectives of this project are to:

  1. Characterize the structural dynamics of the proteins by combining allatom MD dynamics with Markov state model (MSM) theory.
  2. Identify important domains associated with essential, or biologically relevant protein motions.
  3. Mutate residues within these protein domains.
  4. Employ an elaborate method of enhanced MD sampling and produce the wild-type (WT) and mutant (MT) protein energy landscapes (LS). Mutants are necessary to guide the engineering of inactive virial proteins for vaccination.
  5. Explore the protein dynamics at the LS minima.
  6. Propose protein domains as potential epitopes for vaccine development.
  7. Screening of a large database of natural products to find potential inhibitors that bind at the key predicted protein domains, and propose novel molecules as potential inhibitors, based on the structural/ dynamics space and their functional levels.

Project Title: Computational study to guide the development of new SARS-CoV-2 detection hyper-spectral platforms

Project Leader: Dr. Juan Torras, Universitat Politècnica de Catalunya, Spain

Resource Awarded

  • 40 000 000 core hours on Joliot-Curie KNL hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Bio-simulations to develop therapeutics / Biomolecular research to understand the mechanisms of the virus infection

Abstract
The systems proposed to be studied in the project (together with the corresponding methodology) during 6 month, are the following:

  • Silica and gold substrates with different antibodies (IgG, IgM and CR3022. Classical MD). A comparative study among different antibodies and its orientation/interaction with silica and gold surfaces as part of the sandwich silica-antibody-virion-antibody-goldNP detector will be done.
  • Interface Antibody–SARS-CoV-2 spike (S) glycoprotein (classical MD and QM/MM-MD). Antibody specificity and interactions between the epitopes of different antibodies and the antigen will be studied and compared.

Atomistic simulations, which basically consist of conducting computer “experiments” under highly controlled conditions, can anticipate qualitative information about the structure of functionalized multi-dielectric substrates and NPs. Aspects such as the deposition mode of the capture antibody, its orientation (which determines its activity) and specificity, are problems that are at the centre of the development of serological tests. On the other hand, the capture of an antigen by an antibody deposited in dielectric surface is a rare event that, at low concentrations where only a few thousand biomarker molecules are available, determines the effectivity of the therapy. The knowledge developed in this project will allow to obtain novel and better SARS-CoV-2 therapeutics and diagnostics based in antibodies.

Project Title: SPIKE-CAP – Blocking SARS-CoV-2 Spike protein through Computer-Aided design of Peptide inhibitors

Project Leader: Dr. Alfonso Gautieri, Politecnico di Milano, Italy

Resource Awarded

  • 44 000 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Bio-smulations to develop therapeutics and/or vaccines

Abstract
The SPIKE-CAP project aims at the design of antiviral peptides with ultra-high affinity for the virus Spike protein by using high-throughput computational deep scanning mutagenesis. The most promising candidate will be tested by partner lab at MIT using Bio-layer interferometry (BLI) and X-ray crystallography.

Using a computational scanning mutagenesis method developed at Politecnico di Milano and based on Simulated Annealing Molecular Dynamics, we will computationally screen peptide mutations and rank them by binding affinity to S protein, while a Machine Learning algorithm previously developed by the MIT partner will ensure the correct helical folding. Given the sheer amount of potential mutations, we will start the computational screening with the key residue directly involved in the binding of S protein, while progressively extending the design to other positions. We will constantly update the ranking of peptides while the computational screening proceeds and, at weekly intervals, we will synthesize the top scoring candidates. Binding affinity for the S protein will be measured with BLI and crystallography. The project has the potential to identify peptides with ultra-high affinity for the virus S protein, which would outcompete for the binding with human ACE2, thereby preventing virus infection. In addition, the strategy proposed and refined in this project could be helpful for future design of peptidic therapeutics.

Project Title: Targeting the Lysosome-Endosome system to avoid virus entry/exit in cells

Project Leader: Prof. Matteo Ceccarelli, University of Cagliari, Italy

Resource Awarded

  • 7 920 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Biophysics

Abstract
With the objective to understand (i) the mechanism of functioning of TPC2 and (ii) its potentiality as target of antiviral compounds of the flavonoid family, we propose three activities:

    1. Starting from the apo-closed and holo-closed/open structures, explore and sample the TPC2 conformational space with plain MD to (i) prepare a multitude of conformers for successive docking with some flavonoids, and (ii) define quantitatively the open and closed states, using size and hydration number of the hydrophobic gate
    2. Once defined the open state from above, use Metadynamics to understand the functioning of TPC2 investigating the transport of sodium and calcium along the selectivity filter and hydrophobic gate; for divalent calcium we will use a recent parametrization that avoids the use of expensive polarizable MD algorithm and force field; the reconstruction of free energy surface for ions will allow to quantify the concuctivity or flux of ions, as we already done on other systems
    3. Using the open and closed state as defined in (1), investigate the interaction of naringenin with TPC2. The affinity for the protein will be performed with AutoDock Vina on local machines, verified with plain MD, and quantified the kinetics of unbinding with the metadynamics-to-dynamics algorithm, as already done on other systems [11]. We expect to verify up to 5 docking sites.

This project can be generalized to other compounds and to other diseases (cancer and Parkinson).

Project Title: Biomechanic simulations for quantification of the ventilation/perfusion ratio in COVID-19 patients

Project Leader: Dr. Simone Melchionna, Consiglio Nazionale delle Ricerche, Italy

Resource Awarded

  • 30 000 000 core hours on Hawk hosted by GCS at HLRS, Germany

Project Duration: 6 months

Research Field: Bio-Medicine, Bio-Mechanics, Bio-Engineering

Abstract
The present project aims at prognostic judgement of patient management based on the joint usage of pulmonary reconstruction, biomechanical simulations, physiological modelling and ML/AI. The project is a collaboration between academic researchers, AI experts, private entity, and medical doctors from radiology and ICU units. The expected main outcome is to generate predictive values for oxygen and carbon dioxide levels in different ventilation operating scenarios, based on acquired time series, ventilator operating conditions, postures, age, habits etc, doctors can evaluate ventilation efficacy specifically to treat severe cases ahead of time. High-performance simulations on a Tier-0 multi-GPU platform and the wealth of extracted features enable to detect synthetic data for ventilation/perfusion gas exchange and largely enrich the training set by at least one order of magnitude, reaching the sufficient prognostic accuracy.

The results are expected to provide quantitative guidance for ICU pre-admission and postadmission evaluation, informing clinicians about those patients with co-morbidities that require special attention in terms of ventilation operation conditions and maneuvring, helping hospitals to quickly set up the new prognostic system, promote the standardization of work, rationalize the workflow, and improve the efficiency of treatment, as well as medical safety.

Project Title: Identification and Design of drugs interfering with the host translational inhibitor nsp1 of SARS-CoV2

Project Leader: Prof. Francesco Luigi Gervasio, University College London, United Kingdom

Resource Awarded

  • 6 000 000 core hours on Hawk hosted by GCS at HLRS, Germany

Project Duration: 6 months

Research Field: Computational Physics/Chemistry

Abstract
The aim of this project is to explore the druggability of SARS-CoV-2 non-structural protein 1 (Nsp1) and the interaction between Nsp1 and the ribosome 40S unit to guide experimental screening of compound libraries and drug design

Methods that will be used can provide a crucial insight for the rational design and screening of compounds for nsp1 and the nsp1:40S ribosome complex. In so doing, they will pave the way to a complementary strategy for COVID therapeutics.

Project Title: A drug discovery project against the main protease of COVID-19 Project Leader: Prof. Maria João Ramos, University of Porto, Portugal Resource Awarded
  • 11 000 000 core hours on Hawk hosted by GCS at HLRS, Germany
Project Duration: 6 months Research Field: Computational biology, drug discovery Abstract Here, we propose to develop drugs for one particular target, i.e. the main protease of the COVID-19 virus for which there have been made available good resolution x-ray structures in 2020, in the Protein Data Bank. A protease is an enzyme that catalyses proteolysis, i.e. it catalyses the breakdown of proteins into smaller polypeptides or single amino acids. Obviously, if the COVID-19 main protease enzyme is inhibited and cannot function properly, the virus cannot replicate. In fact, the inhibition of a viral main protease is already a very efficient, first-line therapy in other important epidemics, such as AIDS. Therefore, we propose an in-depth computational study, with total length of 4-6 months, to find a shortlist of compounds (leads) with anti-COVID19 activity, i.e. future inhibitors of the main protease of the COVID-19 virus.

Project Title: COVID-DROPLETS

Project Leader: Dr. Gaetano Sardina, Chalmers University of Technology, Sweden

Resource Awarded

  • 20 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Other analyses to understand and mitigate the impact of the pandemic

Abstract
This project aims to investigate the lifetime of expiratory droplets released by an infected individual. Surprisingly, the current recommendations and understanding of the transmission in respiratory infectious diseases are predicated on a simple model developed ninety years ago, thus limiting the effectiveness of the disease containment. The assumptions of the model rely on the simple observation that large droplets (> 10 mm) tend to settle while smaller droplets evaporate faster than they settle in a fraction of second. On the other hand, the complete scenario is more complex; the droplets are emitted in a multiphase turbulent gas cloud that entrains ambient air and are localized in the form of clusters. The local humidity level inside the turbulent flow and the relative competition of closer particles to evaporate, allow the droplets to increase their lifetimes (up to 1000 times) compared with isolated droplets (Bourouiba, JAMA, 2020). The evaporation rate strongly depends on the atmospheric temperature and humidity, and recent preprints are available describing how these climatic variable are linked to the pandemic grow rate. Moreover, a potential correlation between Particulate Matter (PM) pollution and COVID-19 infection spread can exist (Setti et al., preprint).

Project Title: DyCoVin – Interactions and dynamics of SARS-CoV 2 spike-heparin complex

Project Leader: Prof. Rebecca Wade, Heidelberg University, Germany

Resource Awarded

  • 3 520 000 core hours on Marconi100 hosted by CINECA, Italy

Project Duration: 6 months

Research Field: Molecular and Cellular Modeling

Abstract
Our objective is to pinpoint the role of HSPGs in SG1-Cov2 infection using realistic computer simulations. This knowledge will allow us to characterize the structure and dynamics of putative binding patches for heparin-like compounds on the spike receptor, which needs to adopt the open form to bind ACE2.

Our specific aims are to use computational methods, including molecular dynamics simulation (MDS) and docking, for the following three tasks:

  • Simulation of the closed conformation of SG1-Cov2. In contrast to MDS trajectories reported so far that have been performed for an, at most, partially glycosylated spike 1, we will perform simulations for a complete model for the SG1-Cov2 glycoprotein to which we have covalently attached 18 N-glycans on the basis of mass spectrometry studies.
  • Modelling of long-heparin chains (24 monosaccharides) to simulate the interaction between SG1-Cov2 and HSPG and investigate whether this interaction stimulates the opening of the receptor.
  • Design of appropriate heparins for use as putative coronavirus antiviral therapeutics by taking advantage of the basic heparin binding domain present on SG1-Cov2.

We aim to stabilize the receptor in its closed conformation, by: (i) using short heparin chains (up to 6 monosaccharides) which could directly interact with and shield the RBDs of the homotrimeric SG1-Cov2. (ii) using long heparin chains (> 12 monosaccharides) which could decrease the flexibility of the SG1-Cov2 RBD and thereby hinder the conformational changes that are required for the SG1- Cov2 translocation and subsequent opening.

We expect the impact of this approach for treating the viral infection to be high because heparin is already approved by the FDA, used in the treatment of other lung diseases such as pulmonary fibrosis, bronchial asthma and asthma-induced airway hypersensitivity, and recent clinical trials suggest that inhaled heparin for lung diseases is beneficial and safe. For these reasons, aerosol drug administration could provide the advantage of directly delivering heparin to the site of SARS-Cov-2 infection and thereby facilitating the inhibition of the virus/receptor interaction.

Project Title: Exploring Covid19 Infectious Mechanisms and Host Selection Process

Project Leader: Prof. Modesto Orozco, Institute for Research in Biomedicine (IRB Barcelona), Spain

Resource Awarded

  • 6 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Exploring Covid19 Infectious Mechanisms and Host Selection Process

Abstract

We aim to understand the evolutionary path driving the virus from bat to humans, predict differential human sensitivity to infection and the impact of virus mutations in infectivity. Our goal is to predict potential new variants of the virus emerging in a second infective wave and their potential of infectivity

The objectives of this proposal is to fight Covid19 and proximal strains now confined in other mammals: we aim to anticipate virus’s next move and clarify the zoonotic pathway used by virus, its mutational space, as well as to understand different susceptibility to infection of human population and predict genomic changes impacting infectiveness. Molecular dynamics (MD) simulations will provide information on potential cavities in the variants of viral proteins which can be tackled by small drugs. This project involves 4 computational groups (N. López-Bigas and M. Orozco at IRB and R. Badia and J.L. Gelpí at BSC) and experimental groups in Marseille and Milan. We will focus on the entrance of the virus into the host cell, and particularly in the mechanisms linked to RBD recognition by ACE2 and CD147. We aim to determine the impact of genetic changes in the viral RBD and in ACE2/RBD in the recognition of the virus.

Project Title: NANODROP

Project Leader: Prof. Stéphane Zaleski, Sorbonne Université, France

Resource Awarded

  • 1 000 000 core hours on Joliot-Curie Rome hosted by GENCI at CEA, France

Project Duration: 6 months

Research Field: Fluid mechanics – disease propagation

Abstract

Understanding the mechanism of Covid-19 propagation is essential to perform modelling and recommend protective actions. The SARS-Cov-2 is a 100nm particle coated in a bilipidic layer, propelled into the air inside saliva droplets. How the dynamics and physical chemistry of these droplets affects virus transmission is of great importance. Despite some experimental knowledge about the transmission of diseases by aerosols, very little is known about the physics of aerosol behaviour. The proposal would thus allow to better understand the virus transmission mode.

The PRACE Fast Track Call for Proposals for projects requesting computing resources to contribute to the mitigation of the impact of the COVID-19 pandemic received a number of applications that were deemed better suited to a different access mechanism after review. Click the button below to find a list of these redirected projects.

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