The novel coronavirus (SARS-CoV-2) contains a comparatively large RNA genome which encodes an RNA-dependent RNA polymerase (RdRp) for RNA synthesis in the viral genome replication and transcription. Nucleotide analogues can be recruited similarly as natural nucleotide substrates into the active site of the RdRp to interfere with the viral RNA synthesis, thus potentially serve as anti-viral therapeutics. Based on recently solved high-resolution structure of CoV-2 RdRp, we have conducted computational interrogations to probe nucleotide selectivity and fidelity control of the RdRp, employing mainly atomic molecular dynamics (MD) simulations to reveal nucleotide insertion dynamics and energetics of a representative nucleotide analog from Remdesivir, in comparison with natural cognate substrate ATP and noncognate dATP etc.. As current simulations (e.g., using the umbrella sampling method) indicate that varying forcing conditions and initial configurations of the nucleotide binding impact on free energy calculations, further enhanced sampling methods would also be explored. With relative nucleotide binding and insertion energetics of the nucleotide being calculated from the MD simulation, the overall nucleotide selectivity of the RdRp can be further estimated under a stepwise kinetic framework of the nucleotide addition cycle via the chemical master equation approach. Following this line, we pursue comparative studies on additional representative nucleotide analogues, which serve as approved or experimental broad-spectrum antiviral drugs with potential for treatments on the coronaviruses caused diseases.

Revealing nucleotide insertion dynamics, energetics, and selectivity in RNA dependent RNA polymerase of SARS-CoV-2

ACS Fall 2021

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