A Computational Study on the Interaction of NSP10 and NSP14: Unraveling the RNA Synthesis Proofreading Mechanism in SARS-CoV-2, SARS-CoV, and MERS-CoV

Abstract

The interaction of exoribonuclease (ExoN) nonstructural protein (NSP14) with NSP10 co-factors is crucial for high-fidelity proofreading activity of coronavirus replication and transcription. Proofreading function is critical for maintaining the large genomes to ensure replication proficiency; therefore, while maintaining the viral replication fitness, quick resistance has been reported to the nucleotide analogue (NA) drugs. Therefore, targeting the NSP14 and NSP10 interacting interface with small molecules or peptides could be a better strategy to obstruct replication processes of coronaviruses (CoVs). A comparative study on the binding mechanism of NSP10 with the NSP14 ExoN domain of SARS-CoV-2, SARS-CoV, MERS-CoV, and four SARS-CoV-2 NSP14 mutant complexes has been carried out. Protein–protein interaction (PPI) dynamics, per-residue binding free energy (BFE) analyses, and the identification of interface hotspot residues have been studied using molecular dynamics simulations and various computational tools. The BFE of the SARS-CoV NSP14–NSP10 complex was higher when compared to novel SARS-CoV-2 and MERS. However, SARS-CoV-2 NSP14 mutant systems display a higher BFE as compared to the wild type (WT) but lower than SARS-CoV and MERS. Despite the high BFE, the SARS-CoV NSP14–NSP10 complex appears to be structurally more flexible in many regions especially the catalytic site, which is not seen in SARS-CoV-2 and its mutant or MERS complexes. The significantly high residue energy contribution of key interface residues and hotspots reveals that the high binding energy between NSP14 and NSP10 may enhance the functional activity of the proofreading complex, as the NSP10–NSP14 interaction is essential in maintaining the stability of the ExoN domain for the replicative fitness of CoVs. The factors discussed for SARS-CoV-2 complexes may be responsible for NSP14 ExoN having a high replication proficiency, significantly leading to the evolution of new variants of SARS-CoV-2. The NSP14 residues V66, T69, D126, and I201and eight residues of NSP10 (L16, F19, V21, V42, M44, H80, K93, and F96) are identified as common hotspots. Overall, the interface area, hotspot locations, bonded/nonbonded contacts, and energies between NSP14 and NSP10 may pave a way in designing potential inhibitors to disrupt NSP14–NSP10 interactions of CoVs especially SARS-CoV-2.

Molecular Property Diagnostic Suite for COVID-19 (MPDSCOVID-19): an open-source disease-specific drug discovery portal

“…The users can submit the calculation in the main window, and the results will appear in the history panel. information, Protein-Protein Interaction (PPI) [33,34], host protein information, epidemiology, and inhibitors databases.…”

Glycoprotein attachment with host cell surface receptor ephrin B2 and B3 in mediating entry of nipah and hendra virus: a computational investigation

“…15 Various molecular modelling studies have been applied to understand the molecular mechanism of PPI at an atomic level and to decipher the hotspot residues for drug designing and the effect of mutation on a protein's structure and function. [16][17][18][19] The study was evaluated by analysing the binding energy of the trajectory throughout the 250 ns MD simulations, 20 the changes occur in the secondary structure of the PPI complex, identification of hotspot residues from the last 50 ns average structure extracted from the 250 ns MD trajectories.…”