Defining neutralization and allostery by antibodies against COVID-19 variants

Nikhil Kumar Tulsian (), Raghuvamsi Venkata Palur, Xinlei Qian, Yue Gu, Bhuvaneshwari D/O Shunmuganathan, Firdaus Samsudin, Yee Hwa Wong, Jianqing Lin, Kiren Purushotorman, Mary McQueen Kozma, Bei Wang, Julien Lescar, Cheng-I Wang, Ravindra Kumar Gupta, Peter John Bond () and Paul Anthony MacAry ()
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Nikhil Kumar Tulsian: National University of Singapore
Raghuvamsi Venkata Palur: National University of Singapore
Xinlei Qian: National University of Singapore
Yue Gu: National University of Singapore
Bhuvaneshwari D/O Shunmuganathan: National University of Singapore
Firdaus Samsudin: Bioinformatics Institute, Agency for Science, Technology, and Research (A*STAR)
Yee Hwa Wong: Nanyang Technological University
Jianqing Lin: Nanyang Technological University
Kiren Purushotorman: National University of Singapore
Mary McQueen Kozma: National University of Singapore
Bei Wang: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR)
Julien Lescar: Nanyang Technological University
Cheng-I Wang: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR)
Ravindra Kumar Gupta: National University of Singapore
Peter John Bond: National University of Singapore
Paul Anthony MacAry: National University of Singapore

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract The changing landscape of SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. The functional activity of neutralizing antibodies is linked to their quaternary changes occurring as a result of antibody-Spike trimer interactions. Here, we reveal the conformational dynamics and allosteric perturbations linked to binding of novel human antibodies and the viral Spike protein. We identified epitope hotspots, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects on Spike, with implications for neutralization efficacy. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19 and may assist in designing effective antiviral strategies.

Date: 2023
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DOI: 10.1038/s41467-023-42408-x

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