Prediction of the Effects of Nonsynonymous Variants on SARS-CoV-2 Proteins.

Abstract

Background:SARS-CoV-2 virus isa highly transmissible pathogen that causesCOVID-19. Theoutbreak originatedinWuhan, China in December 2019. A number of nonsynonymous mutations located atdifferentSARS-CoV-2 proteinshavebeen reportedby multiple studies.However, therearelimitedcomputationalstudies onthebiological impacts of these mutations on the structure and function of the proteins. Methods:In our study nonsynonymous mutations oftheSARS-CoV-2 genome and their frequencieswere identifiedfrom30,229sequences.Subsequently, theeffects ofthetop10nonsynonymous mutations of different SARS-CoV-2 proteinswere analyzed using bioinformatics toolsincluding co-mutation analysis,prediction oftheprotein structure stabilityand flexibilityanalysis,andprediction oftheprotein functions. Results:Atotal of 231 nonsynonymous mutations were identified from 30,229 SARS-CoV-2 genome sequences. The top10nonsynonymous mutationsaffectingnineamino acid residueswere ORF1a nsp5 P108S, ORF1b nsp12 P323L and A423V, S protein N501Y and D614G, ORF3a Q57H, N protein P151L, R203K and G204R. Many nonsynonymous mutations showedahigh concurrence ratio, suggesting these mutations may evolve together and interact functionally. Our result showedthatORF1a nsp5P108S,ORF3aQ57H and N protein P151Lmutations may be deleterious to thefunctionof SARS-CoV-2 proteins.In addition,ORF1a nsp5P108Sand S proteinD614Gmaydestabilizethe protein structureswhileS protein D614Gmay have a more open conformationcompared to the wild type. Conclusion:The biological consequences of these nonsynonymous mutations of SARS-CoV-2 proteins should be further validated byin vivoandin vitroexperimental studies in the future.