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

  1. Victor Ovchinnikov
  2. Joy E Louveau
  3. John P Barton
  4. Martin Karplus  Is a corresponding author
  5. Arup K Chakraborty  Is a corresponding author
  1. Harvard University, United States
  2. Massachusetts Institute of Technology, United States
Research Article
  • Cited 11
  • Views 2,724
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Cite this article as: eLife 2018;7:e33038 doi: 10.7554/eLife.33038

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 specific classes of evolutionary lineages: 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 to enable evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed.

Article and author information

Author details

  1. Victor Ovchinnikov

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Joy E Louveau

    Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. John P Barton

    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1467-421X
  4. Martin Karplus

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    For correspondence
    marci@tammy.harvard.edu
    Competing interests
    No competing interests declared.
  5. Arup K Chakraborty

    Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    arupc@MIT.EDU
    Competing interests
    Arup K Chakraborty, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1268-9602

Funding

Lawrence Livermore National Laboratory (LLC Award #B620960)

  • Victor Ovchinnikov
  • Joy E Louveau
  • Martin Karplus
  • Arup K Chakraborty

Ragon Institute

  • Joy E Louveau
  • John P Barton
  • Arup K Chakraborty

CHARMM development project

  • Victor Ovchinnikov
  • Martin Karplus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Aleksandra M Walczak, Ecole Normale Superieure, France

Publication history

  1. Received: October 23, 2017
  2. Accepted: February 13, 2018
  3. Accepted Manuscript published: February 14, 2018 (version 1)
  4. Version of Record published: February 27, 2018 (version 2)

Copyright

© 2018, Ovchinnikov et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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