AUTHOR=Lima Neto José Xavier , Bezerra Katyanna Sales , Barbosa Emmanuel Duarte , Araujo Roniel Lima , Galvão Douglas Soares , Lyra Marcelo Leite , Oliveira Jonas Ivan Nobre , Akash Shopnil , Jardan Yousef A. Bin , Nafidi Hiba-Allah , Bourhia Mohammed , Fulco Umberto Laino
TITLE=Investigation of protein-protein interactions and hotspot region on the NSP7-NSP8 binding site in NSP12 of SARS-CoV-2
JOURNAL=Frontiers in Molecular Biosciences
VOLUME=10
YEAR=2024
URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1325588
DOI=10.3389/fmolb.2023.1325588
ISSN=2296-889X
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.