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

Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies.
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Ovchinnikov V, Louveau JE, Barton JP, Karplus M, Chakraborty AK,


Ovchinnikov V, Louveau JE, Barton JP, Karplus M, Chakraborty AK, (click to view)

Ovchinnikov V, Louveau JE, Barton JP, Karplus M, Chakraborty AK,

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eLife 2018 02 147() 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.

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