Preprint Communication Version 1 Preserved in Portico This version is not peer-reviewed

Variable Structural Networks at the Active Site of the SARS-CoV and SARS-CoV2 Main Proteases

Version 1 : Received: 27 March 2020 / Approved: 29 March 2020 / Online: 29 March 2020 (06:22:06 CEST)

How to cite: Krishnamoorthy, N. Variable Structural Networks at the Active Site of the SARS-CoV and SARS-CoV2 Main Proteases. Preprints 2020, 2020030423 (doi: 10.20944/preprints202003.0423.v1). Krishnamoorthy, N. Variable Structural Networks at the Active Site of the SARS-CoV and SARS-CoV2 Main Proteases. Preprints 2020, 2020030423 (doi: 10.20944/preprints202003.0423.v1).

Abstract

The novel coronavirus SARS-CoV2 (CoV2) emerged in December 2019. This virus has 88% genomic similarity with SARS-CoV (CoV), and both viruses largely depend on their main protease (Mpro) to regulate infection. Mpro thus represents an attractive target for anti-SARS drug design. The CoV and CoV2 Mpro are 97% identical at the sequence level, with 12 variable residues, and their X-ray structures appear similar. We thus structurally analysed how these variable residues affect the intra-molecular interactions between key residues in the CoV2 Mpro active-site. Compared to CoV Mpro, the 12 divergent residues in CoV2 Mpro exhibit modified intra-molecular interaction networks that ultimately restructure the molecular micro-environment. These altered networks also indirectly affect the networks of other active-site residues at the entrance (T26, M49 and Q192) and near the catalytic region (F140, H163, H164, M165 and H172) of the Mpro. This suggest CoV2 indirectly (via neighbours) reshape key molecular networks around the Mpro active-site. It seems that the CoV2 Mpro deceives us with its apparent structurally identical to the CoV Mpro while this viral system accumulates mass mutations (12 variable residues) at key positions. Some of these identified CoV2 Mpro networks at the active-site might guide design of efficient CoV2 Mpro inhibitors.

Subject Areas

COVID-19; SARS-CoV2; SARS-CoV; variable residues; main protease; structural analysis

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