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

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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.

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Victor Ovchinnikov

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States

Competing interests
No competing interests declared.
Joy E Louveau

Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
No competing interests declared.
John P Barton

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1467-421X
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.
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.

"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.

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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.