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

Rory Henderson, Brian E. Watts, Hieu N. Ergin, Kara Anasti, Robert Parks, Shi-Mao Xia, Ashley Trama, Hua-Xin Liao, Kevin O. Saunders, Mattia Bonsignori, Kevin Wiehe, Barton F. Haynes and S. Munir Alam ()
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Rory Henderson: Duke University School of Medicine
Brian E. Watts: Duke University School of Medicine
Hieu N. Ergin: Duke University School of Medicine
Kara Anasti: Duke University School of Medicine
Robert Parks: Duke University School of Medicine
Shi-Mao Xia: Duke University School of Medicine
Ashley Trama: Duke University School of Medicine
Hua-Xin Liao: Duke University School of Medicine
Kevin O. Saunders: Duke University School of Medicine
Mattia Bonsignori: Duke University School of Medicine
Kevin Wiehe: Duke University School of Medicine
Barton F. Haynes: Duke University School of Medicine
S. Munir Alam: Duke University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08415-7

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