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

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.
Authors:
ORCiD logo [1] ;  [2] ; ORCiD logo [3] ;  [4] ; ORCiD logo [5]
  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
  2. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, United States
  3. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States, Department of Physics, Massachusetts Institute of Technology, Cambridge, United States, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States
  4. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States, Laboratoire de Chimie Biophysique, ISIS, Universite de Strasbourg, Strasbourg, France
  5. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States, Department of Physics, Massachusetts Institute of Technology, Cambridge, United States, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States, Ragon Institute of MGH, MIT and Harvard, Cambridge, United States, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
Publication Date:
Grant/Contract Number:
LLC Award #B620960; MGH Internal Fund #214931
Type:
Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Volume: 7; Related Information: CHORUS Timestamp: 2018-02-27 10:01:00; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
OSTI Identifier:
1420455
Alternate Identifier(s):
OSTI ID: 1420456