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Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Associated with Increased Transmissibility.
J Mol Biol. 2021 07 23; 433(15):167051.JM

Abstract

The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are structurally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S477N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S477N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.

Authors+Show Affiliations

Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, United States. Electronic address: hhg3@nyu.edu.Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, United States; NYU Abu Dhabi Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates.High-Performance Computing, Center for Research Computing, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.Center for Genomics and Systems Biology, Department of Biology, New York University, 12 Waverly Place, New York, NY 10003, United States; NYU Abu Dhabi Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi 129188, United Arab Emirates. Electronic address: kcg1@nyu.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33992693

Citation

Gan, Hin Hark, et al. "Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface Can Identify High-Affinity Variants Associated With Increased Transmissibility." Journal of Molecular Biology, vol. 433, no. 15, 2021, p. 167051.
Gan HH, Twaddle A, Marchand B, et al. Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Associated with Increased Transmissibility. J Mol Biol. 2021;433(15):167051.
Gan, H. H., Twaddle, A., Marchand, B., & Gunsalus, K. C. (2021). Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Associated with Increased Transmissibility. Journal of Molecular Biology, 433(15), 167051. https://doi.org/10.1016/j.jmb.2021.167051
Gan HH, et al. Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface Can Identify High-Affinity Variants Associated With Increased Transmissibility. J Mol Biol. 2021 07 23;433(15):167051. PubMed PMID: 33992693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Associated with Increased Transmissibility. AU - Gan,Hin Hark, AU - Twaddle,Alan, AU - Marchand,Benoit, AU - Gunsalus,Kristin C, Y1 - 2021/05/14/ PY - 2021/03/10/received PY - 2021/05/06/revised PY - 2021/05/08/accepted PY - 2021/5/17/pubmed PY - 2021/7/22/medline PY - 2021/5/16/entrez KW - SARS-CoV-2 KW - binding affinity KW - combinatorial mutations KW - structural modeling KW - transmissible variants SP - 167051 EP - 167051 JF - Journal of molecular biology JO - J Mol Biol VL - 433 IS - 15 N2 - The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are structurally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S477N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S477N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies. SN - 1089-8638 UR - https://www.unboundmedicine.com/medline/citation/33992693/Structural_Modeling_of_the_SARS_CoV_2_Spike/Human_ACE2_Complex_Interface_can_Identify_High_Affinity_Variants_Associated_with_Increased_Transmissibility_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2836(21)00269-2 DB - PRIME DP - Unbound Medicine ER -