The novel Coronavirus SARS-CoV-2 is a highly pathogenic, (+)-strand RNA virus, responsible for the current pandemic of coronavirus 2019 disease (COVID-19). The life cycle of SARS-CoV-2 is critically dependent upon the activity of the viral RNA-dependent RNA-polymerase (RdRp, also named nsp12), a highly conserved enzyme across an array of viruses, and the primary target of the antiviral drug Remdesivir. A growing number of experimental structures of the SARS-CoV-2 nsp12 have recently become available, suggesting that, while the enzymatic core of its RdRp domain possesses a highly conserved architecture and share similar function with the viral polymerase family, nsp12 also presents some unique structural features, such as the formation of a multi-subunit replication-transcription complex (RTC) with protein cofactors nsp7 and nsp8. We combined molecular dynamics simulations, binding site detection and computational docking of known antiviral drugs to unravel the dynamics and function of the SARS-CoV-2 RdRp in complex with protein cofactors nsp7 and nsp8. Our simulations revealed signature motions of functional RdRp elements, as well as highlighted the role of close contacts between conserved polymerase subdomains and cofactor interface domains. Furthermore, our structural analyses of RTC complexes, combined with simulation trajectories, allowed characterizing and prioritizing hot spots suitable for antiviral drug binding. Our results provide the foundations to design/repurpose new therapeutics targeting viral RdRp domains.

Computational investigations of the RNA-dependent RNA polymerase of SARS-CoV-2 reveal motion of functional elements and characterize hot spots for antiviral drug binding

ACS Fall 2021

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