Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants

James W. Saville, Dhiraj Mannar, Xing Zhu, Shanti S. Srivastava, Alison M. Berezuk, Jean-Philippe Demers, Steven Zhou, Katharine S. Tuttle, Inna Sekirov, Andrew Kim, Wei Li, Dimiter S. Dimitrov and Sriram Subramaniam ()
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James W. Saville: University of British Columbia
Dhiraj Mannar: University of British Columbia
Xing Zhu: University of British Columbia
Shanti S. Srivastava: University of British Columbia
Alison M. Berezuk: University of British Columbia
Jean-Philippe Demers: University of British Columbia
Steven Zhou: University of British Columbia
Katharine S. Tuttle: University of British Columbia
Inna Sekirov: BC Centre for Disease Control
Andrew Kim: University of Pittsburgh School of Medicine
Wei Li: University of Pittsburgh School of Medicine
Dimiter S. Dimitrov: University of Pittsburgh School of Medicine
Sriram Subramaniam: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

Date: 2022
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DOI: 10.1038/s41467-022-28324-6

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