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Title: Using physics to understand and fight viruses

Abstract: The ongoing COVID-19 pandemic has highlighted how viruses can cause human disease, with dramatic and global consequences. Here, I will present two projects where we have used single-molecule approaches to investigate aspects of the life cycles of two notorious viruses: SARS-CoV-2 and HIV.

In the first project, we have developed a tethered ligand assay to investigate how SARS-CoV-2 attaches to human cells. Our assay comprises the tip of the Spike protein and the human receptor protein ACE2 connected by a peptide linker. Using magnetic tweezers and AFM force spectroscopy as well as steered molecular dynamics simulations, we obtain a comprehensive view of the force stability of the critical first interaction of the virus with our cells (Bauer, Gruber, et al. PNAS 2022). We find that SARS-CoV-2 (which causes COVID-19) can withstand higher forces compared to SARS-CoV-1 (which was responsible for the 2002/03 pandemic), which helps explain the different infection patterns of the two viruses. Investigating the current variants of concern, we find differences in force stability that help rationalize the epidemiology of the different variants (Gruber et al., unpublished).

In a second line of research, we have used magnetic tweezers and AFM imaging assays to investigate the interactions of retroviral integrases –the key enzymes that catalyzes the insertion of the viral DNA into the genome of the host– with DNA. The assays provide a comprehensive view of the free energy landscape of retroviral integration for prototype foamy virus (Vanderlinden et al. Nature Comm. 2019). For HIV, we find that, in addition to it well known catalytic role, integrase serves an unexpected structural role and can efficiently condense DNA into biomolecular condensates (Kolbeck et al., unpublished).