Selection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies.

Published online

Journal Article

Somatic mutations within antibody variable and framework regions (FWR) can alter thermostability and structural flexibility, but their impact on functional potency is unclear. Here we study thermostability and use molecular dynamics (MD) simulations to assess the role of FWR mutations during maturation of HIV-1 broadly neutralizing antibodies (bnAbs). The tested bnAbs show lower thermostability than their unmutated ancestor antibodies. FWR mutations in the Fab elbow region are frequently observed in HIV-1 bnAbs and MD simulations show that such FWR mutations alter interdomain flexibility in two HIV-1 bnAbs. In a CD4-binding site lineage, reversion mutations result in a loss of neutralization potency in an early intermediate and affinity-matured bnAb against autologous and heterologous Tier-2 viruses, respectively. Elbow region reversion mutations in a glycan-V3 bnAb modestly reduces potency against an autologous virus isolate. Thus, selection of mutations in the Fab elbow region impacts interdomain conformational flexibility and paratope plasticity during bnAb development.

Full Text

Duke Authors

Cited Authors

  • Henderson, R; Watts, BE; Ergin, HN; Anasti, K; Parks, R; Xia, S-M; Trama, A; Liao, H-X; Saunders, KO; Bonsignori, M; Wiehe, K; Haynes, BF; Alam, SM

Published Date

  • February 8, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 654 -

PubMed ID

  • 30737386

Pubmed Central ID

  • 30737386

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-08415-7

Language

  • eng

Conference Location

  • England