Investigation of protein-protein interactions and hotspot region on the NSP7-NSP8 binding site in NSP12 of SARS-CoV-2

José Xavier Lima Neto; Katyanna Sales Bezerra; Emmanuel Duarte Barbosa; Roniel Lima Araujo; Douglas Soares Galvão; Marcelo Leite Lyra; Jonas Ivan Nobre Oliveira; Shopnil Akash; Yousef A Bin Jardan; Hiba-Allah Nafidi; Mohammed Bourhia; Umberto Laino Fulco

doi:10.3389/fmolb.2023.1325588

Investigation of protein-protein interactions and hotspot region on the NSP7-NSP8 binding site in NSP12 of SARS-CoV-2

Front Mol Biosci. 2024 Jan 18:10:1325588. doi: 10.3389/fmolb.2023.1325588. eCollection 2023.

Affiliations

¹ Department of Biophysics and Pharmacology, Bioscience Center, Federal University of Rio Grande do Norte, Natal, Brazil.
² Applied Physics Department, University of Campinas, Campinas, São Paulo, Brazil.
³ Physics Institute, Federal University of Alagoas, Maceió, Brazil.
⁴ Department of Pharmacy, Daffodil International University, Dhaka, Bangladesh.
⁵ Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁶ Department of Food Science, Faculty of Agricultural and Food Sciences, Laval University, Quebec City, QC, Canada.
⁷ Department of Chemistry and Biochemistry, Faculty of Medicine and Pharmacy, Ibn Zohr University, Laayoune, Morocco.

Abstract

Background: The RNA-dependent RNA polymerase (RdRp) complex, essential in viral transcription and replication, is a key target for antiviral therapeutics. The core unit of RdRp comprises the nonstructural protein NSP12, with NSP7 and two copies of NSP8 (NSP81 and NSP82) binding to NSP12 to enhance its affinity for viral RNA and polymerase activity. Notably, the interfaces between these subunits are highly conserved, simplifying the design of molecules that can disrupt their interaction. Methods: We conducted a detailed quantum biochemical analysis to characterize the interactions within the NSP12-NSP7, NSP12-NSP81, and NSP12-NSP82 dimers. Our objective was to ascertain the contribution of individual amino acids to these protein-protein interactions, pinpointing hotspot regions crucial for complex stability. Results: The analysis revealed that the NSP12-NSP81 complex possessed the highest total interaction energy (TIE), with 14 pairs of residues demonstrating significant energetic contributions. In contrast, the NSP12-NSP7 complex exhibited substantial interactions in 8 residue pairs, while the NSP12-NSP82 complex had only one pair showing notable interaction. The study highlighted the importance of hydrogen bonds and π-alkyl interactions in maintaining these complexes. Intriguingly, introducing the RNA sequence with Remdesivir into the complex resulted in negligible alterations in both interaction energy and geometric configuration. Conclusion: Our comprehensive analysis of the RdRp complex at the protein-protein interface provides invaluable insights into interaction dynamics and energetics. These findings can guide the design of small molecules or peptide/peptidomimetic ligands to disrupt these critical interactions, offering a strategic pathway for developing effective antiviral drugs.

Keywords: NSP7-NSP8 binding site; SARS CoV-2; and infectious disease; computational biology; drug design.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors would like to extend their sincere appreciation to the Researchers Supporting Project, King Saud University, Riyadh, Saudi Arabia for funding this work through the project number (RSP2024R457).