Comparative Structural Analysis of Human ACE2 Receptor with Spike Protein of SARS-CoV-2 Variants: Implications to Understand Infectivity of the Virus

Tirthankar Koley, Arunima Goswami, Manoj Kumar, Neelam Upadhyay, Gururao Hariprasad Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, IndiaCorrespondence: Gururao Hariprasad, Tel +91-11-26594240, Fax +91-11-26588663, Email dr.hariprasadg@gmail.comPurpose: Spike protein on SARS-CoV-2 virus plays an integral part during infection as cell entry depends on binding of this protein to human ACE2 receptor. Understanding of infectivity by these variants necessitates a comparative structural analysis of complexes of spike protein-receptor binding domain (RBD) of these variants to receptor.Methodology: Wild type SARS-CoV-2 spike protein sequence was retrieved from the UniProt database, and mutations of five variants at receptor binding domain were manually incorporated and aligned using Clustal Omega. Crystal structure complexes of human ACE2 receptor with spike protein RBD domain of SARS-CoV-2 variants of wild type, α, β, and δ were extracted from the RCSB database. Wild type SARS-CoV-2 complex with receptor was used as template to generate model complexes of receptor with spike protein RBD of γ and omicron variants through WinCoot program. These were energy minimized and validated and molecular dynamic simulation was performed using Desmond simulation program.Results: Mutations are distributed across the entire length of RBD, but the maximum number of mutations are seen at 11 positions within binding interface motifs of six variant sequences. Interface of spike protein RBDs with human ACE2-receptor shows different mix of hydrogen bonded and ionic interactions. Alpha and β variants have few interactions, while γ and δ variants have higher number of interactions compared to wild type variant. Omicron variant, with 10 polar interactions including two ionic bonds, has the highest binding energy.Conclusion: Different mutations on RBD of spike protein results in varying quantity and quality of interactions, thereby affecting potency of each variant. Variations in binding are due to interactions of mutant residues and induced conformational changes on loops of RBDs. Variants α and β have a low potency, while, γ, δ, and omicron have a higher potency. These results correlate with viral infectivity and place clinical observations in the right perspective.Keywords: SARS-CoV-2, variants, omicron, mutations, spike protein, human ACE2 receptor, interactions, binding, infectivity