Extended antibody-framework-to-antigen distance observed exclusively with broad HIV-1-neutralizing antibodies recognizing glycan-dense surfaces

Myungjin Lee, Anita Changela, Jason Gorman, Reda Rawi, Tatsiana Bylund, Cara W. Chao, Bob C. Lin, Mark K. Louder, Adam S. Olia, Baoshan Zhang, Nicole A. Doria-Rose, Susan Zolla-Pazner, Lawrence Shapiro, Gwo-Yu Chuang () and Peter D. Kwong ()
Additional contact information
Myungjin Lee: National Institutes of Health
Anita Changela: National Institutes of Health
Jason Gorman: National Institutes of Health
Reda Rawi: National Institutes of Health
Tatsiana Bylund: National Institutes of Health
Cara W. Chao: National Institutes of Health
Bob C. Lin: National Institutes of Health
Mark K. Louder: National Institutes of Health
Adam S. Olia: National Institutes of Health
Baoshan Zhang: National Institutes of Health
Nicole A. Doria-Rose: National Institutes of Health
Susan Zolla-Pazner: Icahn School of Medicine at Mount Sinai
Lawrence Shapiro: National Institutes of Health
Gwo-Yu Chuang: National Institutes of Health
Peter D. Kwong: National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Antibody-Framework-to-Antigen Distance (AFAD) – the distance between the body of an antibody and a protein antigen – is an important parameter governing antibody recognition. Here, we quantify AFAD for ~2,000 non-redundant antibody-protein-antigen complexes in the Protein Data Bank. AFADs showed a gaussian distribution with mean of 16.3 Å and standard deviation (σ) of 2.4 Å. Notably, antibody-antigen complexes with extended AFADs (>3σ) were exclusively human immunodeficiency virus-type 1 (HIV-1)-neutralizing antibodies. High correlation (R2 = 0.8110) was observed between AFADs and glycan coverage, as assessed by molecular dynamics simulations of the HIV-1-envelope trimer. Especially long AFADs were observed for antibodies targeting the glycosylated trimer apex, and we tested the impact of introducing an apex-glycan hole (N160K); the cryo-EM structure of the glycan hole-targeting HIV-1-neutralizing antibody 2909 in complex with an N160K-envelope trimer revealed a substantially shorter AFAD. Overall, extended AFADs exclusively recognized densely glycosylated surfaces, with the introduction of a glycan hole enabling closer recognition.

Date: 2021
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DOI: 10.1038/s41467-021-26579-z

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