BioExcel Supports Range of COVID-19 Research Activities
Rossen Apostolov, PDC
The BioExcel Centre of Excellence for Computational Biomolecular Research provides support to academic and industrial researchers in the areas of molecular dynamics simulations, biomolecular integrative modelling, free energy calculations and docking. In recent months BioExcel has launched a series of activities to support research on the SARS-CoV-2 virus to assist with the global fight against COVID-19.
The ongoing pandemic associated with the virus has already affected most of the world in a dramatic way. It endangers the lives of many people, and puts a tremendous strain on medical systems, while the second-order effects on the economy and daily life have been equally devastating. Governments and the private sector are undertaking massive concerted efforts to tackle the crisis. Unquestionably, the discovery of a vaccine or cure will be of paramount importance when it comes to controlling the spread of the illness in the long-term.
To this end, BioExcel experts are partnering with numerous international initiatives to lend all of our advanced software applications and expertise to the search for a vaccine or cure and BioExcel's partners are actively working on a range of modelling and simulation projects related to SARS-CoV-2.
Sharing data for COVID-19 applications has become more vital than ever due to the urgent need to identify compounds (known as “leads”) which have pharmacological or biological activity that means they could be suitable for developing therapies, diagnostics, and vaccines for COVID-19. To maximize the impact of molecular simulation methods in this crisis, BioExcel members have signed the international community letter which aims to connect researchers and improve communication between simulation, experimental and clinical data investigators.
Nostrum Biodiscovery (NBD) is focusing on screening its proprietary virtual library, ChemistriX, as well as other open libraries (like Zinc), into the 3C main protease of SARS-CoV-2; blocking this enzyme would mean the virus could not replicate efficiently. For this reason, NBD is using a hierarchical docking approach combining Glide (a docking tool from Schrödinger) with PELE, NBD’s proprietary Monte Carlo code which is a computational protocol that has shown remarkable results in international blind competitions. In addition, this approach is highly parallel and can take advantage of the supercomputer facilities at the Barcelona Supercomputing Center (BSC). The work is being done in collaboration with the Electronic and Atomic Protein Modelling Group led by Victor Guallar at BSC, and contributes altruistically to the EXSCALATE4CoronaVirus consortium. Within the same consortium, the KTH Royal Institute of Technology is providing GROMACS and consultancy expertise to meet the needs of researchers who have to tailor molecular dynamics simulations for large-scale executions.
The Institute of Neuroscience and Medicine (INM-9) at Jülich Research Center (JSC) is using local supercomputing resources to identify ligands (molecules) that bind to proteins contributing to the coronavirus-host interactions, which are key to viral pathogenesis. The team (together with CINECA, Bologna, Italy) is currently performing virtual ligand screening experiments (in parallel on different proteins) on the JSC high-performance computing (HPC) systems. The resulting libraries of molecules will then undergo in-vitro testing.
Researchers from the University of Jyväskylä (JYU), Finland, are performing large-scale molecular dynamics simulations of the spike protein from the SARS-CoV-2 virus binding to the human ACE2 receptor as a first step to understand the interactions that control host cell recognition in lung tissue. (The spike protein is the main protein that the virus uses to invade human cells. It binds to another protein, known as a receptor, which is part of the human cell membrane, then the viral membrane fuses with the human cell membrane, allowing the genome of the virus to enter human cells and begin infection.) The group is also investigating the spike protein complexed with aptamer candidates to systematically search for oligonucleotides that could selectively bind to the spike protein and thus prevent it from binding to a human cell. (Aptamers are oligonucleotide or peptide molecules that bind to a specific target molecule.) The large-scale simulations are being performed using custom workflows, which are running on HPC resources at CSC in Finland. Moreover, the workflows and protocol used in this project will be readily available if future outbreaks of other infections occur. The project involves a team of specialists in chemistry, molecular modelling, and infectious diseases as well as in aptamer selection and modification. Collaborators include researchers from Moscow State University and the Russian Academy of Sciences, who have a strong track record in developing DNA aptamers for diagnostic and therapeutic purposes.
In a parallel project, JYU researchers (including Petri Pihko, an expert in organic synthesis, and Varpu Marjomäki, a virology specialist) are working on inhibiting the SARS-CoV-2 RdRP (which is the enzyme that assists the virus to replicate its RNA) with nucleotide analogues. The RdRP structure was recently resolved to a fine degree and, since then, the group has been performing simulations to investigate the viability of various potential approaches that might stop the virus from replicating.
A team at the Max Planck Institute for Biophysical Chemistry, Göttingen, has started to simulate the complex of the SARS-CoV-2 coronavirus spike protein bound to the human ACE2 receptor using a combination of GROMACS and PMX. Their goal is to design a derivative of ACE2 with enhanced affinity for the SARS-CoV-2 spike protein for either diagnostic or therapeutic purposes.
The Worldwide e-Infrastructure for NMR and Structural Biology (WeNMR) portal, developed and run by BioExcel's partners at Utrecht University, has seen an increase in registrations over recent weeks with many users indicating they intend to use it for COVID-19 projects. The HADDOCK WeNMR team is already involved in several collaborations ranging from drug screening against the protease to modelling COVID-19-related protein-protein interactions. For this purpose, together with EGI/EOSC experts, the team is looking both into expanding the processing capacity of the HADDOCK portals and providing customized solutions to support researchers. These might take the form of dedicated virtual clusters with a HADDOCK front end running on EOSC cloud resources, and customized virtual machines with ready-to-run local HADDOCK installations for experienced users wanting to use the software at the command line.
The Institute for Research in Biomedicine Barcelona (IRB Barcelona) is working on understanding how the virus has evolved by comparing its structure/genome to other corona-viruses, including the earlier SARS-CoV. Their work, which includes MD simulations, as well as bioinformatic analysis, aims to reveal how the virus evolves and how the hosts are selected by identifying key structural determinants and pathogenic mutations that have occurred going from one viral strain to another - which is also of utmost importance for future pandemic surveillance. The information from these studies will be used to identify virus inhibition opportunities by means of in silico drug screening, starting from known and commercially available drugs first. This work is being undertaken in collaboration with Roberto Burioni’s laboratory for viral research in San Raffaele, Italy.