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

Victor Ovchinnikov, Joy E. Louveau, John P. Barton, Martin Karplus, Arup K. Chakraborty

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish
Article numbere33038
JournaleLife
Volume7
DOIs
StatePublished - 14 Feb 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© Ovchinnikov et al.

Funding

Financial support for this work was provided by a grant from the Lawrence Livermore National Laboratory (AKC, MK, VO, JL) the Ragon Institute of MGH, MIT, and Harvard (AKC, JPB), and the CHARMM Development Project (MK, VO). Financial support for this work was provided by a grant from the Lawrence Livermore National Laboratory (AKC, MK, VO, JL) the Ragon Institute of MGH, MIT, and Harvard (AKC, JPB), and the CHARMM Development Project (MK, VO). Lawrence Livermore National Laboratory LLC Award #B620960 Victor Ovchinnikov Joy E Louveau Martin Karplus Arup K Chakraborty Ragon Institute of MGH, MIT and Harvard MGH Internal Fund #214931 Joy E Louveau John P Barton Arup K Chakraborty CHARMM Development Pro- ject Victor Ovchinnikov Martin Karplus.

FundersFunder number
AKC
Massachusetts General Hospital#214931
Lawrence Livermore National Laboratory#B620960
Massachusetts Institute of Technology
Ragon Institute of MGH, MIT and Harvard

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