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bioRxiv · 10.1101/2020.12.12.422477

Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV-2 non-structural proteins

Dubanevics, I.·Heaton, C.·Riechmann, C.·McLeish, T. C. B.
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic, has no vaccine or antiviral drugs available to the public, at the time of writing. The virus non-structural proteins are promising drug targets because of their vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which covalently and competitively bind the active site of the non-structural proteins, but little has been done to address regions other than the active site, i.e. for non-competitive inhibition. Here we extend previous work on the SARS-CoV-2 Mpro (nsp5) to three other SARS-CoV-2 proteins: host shutoff factor (nsp1), papain-like protease (nsp3, also known as PLpro) and RNA-dependent RNA-polymerase (nsp12, also known as RdRp) in complex with nsp7 and nsp8 cofactors. Using open-source software (DDPT) to construct Elastic Network Models (ENM) of the chosen proteins we analyse their fluctuation dynamics and thermodynamics, as well as using this protein family to study convergence and robustness of the ENM. Exhaustive 2-point mutational scans of the ENM and their effect on fluctuation free energies suggest several new candidate regions, distant from the active site, for control of the proteins function, which may assist the drug development based on the current small molecule binding screens. The results also provide new insights, including non-additive effects of double-mutation or inhibition, into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure.

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Dubanevics, I., Heaton, C., Riechmann, C., McLeish, T. C. B.. 2020-12-14. Computational Analysis of Dynamic Allostery and Control in the three SARS-CoV-2 non-structural proteins. https://doi.org/10.1101/2020.12.12.422477

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