1st International and 10th National Iranian Conference on Bioinformatics

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Computational saturation mutagenesis to predict the effects of systematic mutations on the stability and binding affinity of nonstructural proteins 7 and 8 in SARS-CoV-2

Paper ID : 1391-ICB10

Authors:

Fatemeh Arabi Jeshvaghani *, Fatemeh Javadi-Zarnaghi

دانشگاه اصفهان

Abstract:

The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by protein-protein interactions of nonstructural proteins (nsps) and nsp-viral RNAs. The central component of replication machinery in SARS-CoV-2 is nsp12 with RNA-dependent RNA polymerase (RdRp) activity that catalyzes the synthesis of viral RNAs. Nsp7 and nsp8 as cofactors of RdRp play vital roles in stimulating the polymerase activity of RdRp and promoting its processivity [1]. In this study, we analyzed the effects of all possible mutations (a total of 3724 mutations) generated by the computational saturation mutagenesis of all residues in nsp7 and nsp8 proteins of SARS-CoV-2 to all other 19 residues on the stability of proteins and protein-protein binding affinity. mCSM-PPI2 [2] server was used to predict the effects of missense mutations on nsp7-nsp8 binding affinity. The impacts of the generated systematic mutations on stability and flexibility of investigated proteins were predicted by structure-based prediction tools including DynaMut [3], mCSM [4], SDM [5], and CUPSAT [6] servers as well as PROVEAN [7] and I-Mutant 2.0 [8] as sequence-based prediction tools. ConSurf [9] was used for analyzing the evolutionary conservation of the residues. A significant majority of mutations have the potential to destabilize the interaction of nsp7 and nsp8. K2P, M52D, and L56G mutations in nsp7 and L108D, I111D, and L96D mutations in nsp8 were predicted to significantly decrease the nsp7-nsp8 binding affinity. Mutations in highly conserved interface residues of nsp7-nsp8 were predicted to considerably decrease the stability and flexibility of proteins. This study provides comprehensive insights into the consequences of mutations in nsp7 and nsp8 proteins with importance in antiviral design and development for COVID-19 or future possible outbreaks related to coronaviruses.

Keywords:

SARS-CoV-2; nsp7-nsp8; Computational Saturation mutagenesis; COVID-19; Missense mutation

Status : Paper Accepted (Poster Presentation)