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Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies

Author(s)
Karplus, Martin; Ovchinnikov, Victor A; Louveau, Joy E; Barton, John P; Chakraborty, Arup K
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Downloadelife-33038-v2.pdf (2.192Mb)
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Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/
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Abstract
Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest that there are different classes of evolutionary lineages for the bnAbs. If germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs. If the germline B cells exhibit weak/moderate affinity for conserved residues, an initial increase in flexibility via framework mutations may be required for the evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed.
Date issued
2018-02
URI
http://hdl.handle.net/1721.1/115144
Department
Institute for Medical Engineering and Science; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Chemical Engineering; Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Department of Physics
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Ovchinnikov, Victor et al. “Role of Framework Mutations and Antibody Flexibility in the Evolution of Broadly Neutralizing Antibodies.” eLife 7 (February 2018): e33038 © Ovchinnikov et al
Version: Final published version
ISSN
2050-084X

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