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[Article series] The experts behind Luxembourg's COVID-19 fight

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Publié le lundi 22 juin 2020

Alexandre Tkatchenko is the principal investigator of a large international consortium of physicists, chemists, mathematicians and computer scientists, aiming to investigate the fundamental mechanisms of adhesion of SARS-CoV-2 coronavirus spike proteins to human cell membrane receptors. The consortium is actively looking for funding its activities with several ongoing applications for academic and industrial funding, as well as Tier-0 high performance computer resources.

Prof. Alexandre Tkatchenko explains the project in more details. 

1)     Could you tell us more about your background and expertise? 

I am leading the Theoretical Chemical Physics group in the Department of Physics and Materials Science (DPhyMS). My group develops novel methodologies and undertakes ambitious computational projects to address fundamental and challenging aspects of systems at the intersection of physics, chemistry, and biology. The key goal of our work is to bring quantum-mechanical level of insight and accuracy to large and complex systems. This is achieved by unifying physical theories at varying spatial and temporal scales and by combining first-principles quantum methods, coarse-grained statistical approaches, as well as developing novel mathematical and computational techniques. My group includes physicists, chemists, mathematicians, and computer scientists, and we collaborate with many leading researchers across the globe. 

2)     How is your expertise relevant in the current COVID context? 

The COVID-19 disease is caused by the SARS-CoV-2 coronavirus. A crucial step in the infection is the adhesion of the spike protein of SARS-CoV-2 to the ACE2 receptors located on the human cell membrane. This adhesion mechanism is similar to the previous SARS-CoV-1 coronavirus in 2003, however the current SARS-CoV-2 coronavirus is substantially more infectious. Currently, an experimentally proposed hypothesis is that the high infection rate is caused by a much increased affinity of SARS-CoV-2 spike protein to our cell receptors. However, this remains a hypothesis and the fundamental atomistic adhesion mechanisms of viruses to human cells remain largely unknown. This is where my group's expertise is key. We have already developed state-of-the-art models to calculate adhesive forces between nanoscale objects that have been successfully used by many groups worldwide. 

However, studying the adhesion mechanism between SARS-CoV-2 and ACE2 receptors in atomistic detail presents a wealth of new challenges for us: the systems are much larger containing hundreds of thousands of atoms, the adhesive interface region is dynamic involving the possible flow of water, and many possible adhesion scenarios are possible and must be considered in their fully atomistic picture. All these challenges call for a truly interdisciplinary and multiscale approach for understanding the coronavirus adhesion mechanism. This project has implications for the current COVID-19 pandemic, but will also provide the missing fundamental understanding of how viruses interact with human cell receptors in the long term

3)     What is your specific role in ongoing COVID projects? 

In collaboration with many other leading research groups in Luxembourg and worldwide, since March 2020 we have started to build computational models for studying the adhesion mechanism between SARS-CoV-2 spike protein and ACE2 human cell receptors.

At this moment we have already identified several adhesion motifs (see Figure) and we are about to start quantum-mechanical calculations to estimate the free energy of adhesion. We expect first results to be obtained in the course of summer 2020. 

4)     Could you tell us more about your collaborators? 

This project lies within the Physics Meets Biology efforts, under the initiative Complex Living Systems. The work is done by two PhD students in my group (Martin Stoehr and Justin Diamond) in collaboration with Dr. Thais Arns and the group of Alexander Skupin at the Luxembourg Centre for Systems Biomedicine (LCSB), who is already involved in a number of ongoing projects under the COVID-19 initiative in Luxembourg. In addition, our project requires state-of-the-art high performance computing and machine learning expertise. 

This is provided by a strong collaboration with the group of Prof. Klaus-Robert Mueller at TU Berlin and Google Brain Berlin. Finally, the group of Prof. Sameer Varma from the University of South Florida, provides the much needed expertise on molecular dynamics and protein-protein interactions.