Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies
- Harvard University, United States
- Massachusetts Institute of Technology, United States
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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 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
John P Barton
Arup K Chakraborty
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
- Aleksandra M Walczak, Reviewing Editor, Ecole Normale Superieure, France
Publication history
- Received: October 23, 2017
- Accepted: February 13, 2018
- Accepted Manuscript published: February 14, 2018 (version 1)
- 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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