Defining neutralization and allostery by antibodies against COVID-19 variants

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 antibod...

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Main Authors: Tulsian, Nikhil Kumar, Palur, Raghuvamsi Venkata, Qian, Xinlei, Gu, Yue, Bhuvaneshwari D/O Shunmuganathan, Samsudin, Firdaus, Wong, Yee Hwa, Lin, Jianqing, Purushotorman, Kiren, Kozma, Mary McQueen, Wang, Bei, Lescar, Julien, Wang, Cheng-I, Gupta, Ravindra Kumar, Bond, Peter John, MacAry, Paul Anthony
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/173785
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spelling sg-ntu-dr.10356-1737852024-03-04T15:32:07Z Defining neutralization and allostery by antibodies against COVID-19 variants Tulsian, Nikhil Kumar Palur, Raghuvamsi Venkata Qian, Xinlei Gu, Yue Bhuvaneshwari D/O Shunmuganathan Samsudin, Firdaus Wong, Yee Hwa Lin, Jianqing Purushotorman, Kiren Kozma, Mary McQueen Wang, Bei Lescar, Julien Wang, Cheng-I Gupta, Ravindra Kumar Bond, Peter John MacAry, Paul Anthony School of Biological Sciences NTU Institute of Structural Biology Medicine, Health and Life Sciences COVID-19 Allosterism 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. Published version This work used computational resources of the National Supercomputing Centre (NSCC), Singapore (https://www.nscc.sg), the A*STAR Computational Resource Centre (A*CRC), and the supercomputer Fugaku provided by RIKEN through the HPCI System Research Project (Project ID: hp220297) awarded to P.J.B. and F.S. This study is supported by COVID-19 (R-571-000-081-213) and SCOPE (R-711-000-058-598) grants awarded to P.A.M. by National Medical Research Council, Singapore; FY21 CG HTPO SEED ID BII C211418001 funded by A*STAR awarded to P.J.B., and AME YIRG (A2084c0159) grant funded by A*STAR awarded to F.S. R.V.P., F.S., and P.J.B. were supported by BII (A*STAR) core funds. 2024-02-27T05:35:00Z 2024-02-27T05:35:00Z 2023 Journal Article Tulsian, N. K., Palur, R. V., Qian, X., Gu, Y., Bhuvaneshwari D/O Shunmuganathan, Samsudin, F., Wong, Y. H., Lin, J., Purushotorman, K., Kozma, M. M., Wang, B., Lescar, J., Wang, C., Gupta, R. K., Bond, P. J. & MacAry, P. A. (2023). Defining neutralization and allostery by antibodies against COVID-19 variants. Nature Communications, 14(1), 6967-. https://dx.doi.org/10.1038/s41467-023-42408-x 2041-1723 https://hdl.handle.net/10356/173785 10.1038/s41467-023-42408-x 37907459 2-s2.0-85175593879 1 14 6967 en Nature Communications © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
COVID-19
Allosterism
spellingShingle Medicine, Health and Life Sciences
COVID-19
Allosterism
Tulsian, Nikhil Kumar
Palur, Raghuvamsi Venkata
Qian, Xinlei
Gu, Yue
Bhuvaneshwari D/O Shunmuganathan
Samsudin, Firdaus
Wong, Yee Hwa
Lin, Jianqing
Purushotorman, Kiren
Kozma, Mary McQueen
Wang, Bei
Lescar, Julien
Wang, Cheng-I
Gupta, Ravindra Kumar
Bond, Peter John
MacAry, Paul Anthony
Defining neutralization and allostery by antibodies against COVID-19 variants
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Tulsian, Nikhil Kumar
Palur, Raghuvamsi Venkata
Qian, Xinlei
Gu, Yue
Bhuvaneshwari D/O Shunmuganathan
Samsudin, Firdaus
Wong, Yee Hwa
Lin, Jianqing
Purushotorman, Kiren
Kozma, Mary McQueen
Wang, Bei
Lescar, Julien
Wang, Cheng-I
Gupta, Ravindra Kumar
Bond, Peter John
MacAry, Paul Anthony
format Article
author Tulsian, Nikhil Kumar
Palur, Raghuvamsi Venkata
Qian, Xinlei
Gu, Yue
Bhuvaneshwari D/O Shunmuganathan
Samsudin, Firdaus
Wong, Yee Hwa
Lin, Jianqing
Purushotorman, Kiren
Kozma, Mary McQueen
Wang, Bei
Lescar, Julien
Wang, Cheng-I
Gupta, Ravindra Kumar
Bond, Peter John
MacAry, Paul Anthony
author_sort Tulsian, Nikhil Kumar
title Defining neutralization and allostery by antibodies against COVID-19 variants
title_short Defining neutralization and allostery by antibodies against COVID-19 variants
title_full Defining neutralization and allostery by antibodies against COVID-19 variants
title_fullStr Defining neutralization and allostery by antibodies against COVID-19 variants
title_full_unstemmed Defining neutralization and allostery by antibodies against COVID-19 variants
title_sort defining neutralization and allostery by antibodies against covid-19 variants
publishDate 2024
url https://hdl.handle.net/10356/173785
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