Somatic Hypermutation-Induced Changes in the Structure and Dynamics of HIV-1 Broadly Neutralizing Antibodies

• Published in: Structure (London) 2016-08, Vol.24 (8), p.1346-1357
• Main Authors: Davenport, Thaddeus M., Gorman, Jason, Joyce, M. Gordon, Zhou, Tongqing, Soto, Cinque, Guttman, Miklos, Moquin, Stephanie, Yang, Yongping, Zhang, Baoshan, Doria-Rose, Nicole A., Hu, Shiu-Lok, Mascola, John R., Kwong, Peter D., Lee, Kelly K.
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - chemistry; Antibodies, Viral - genetics; Antibodies, Viral - immunology; HIV-1 - immunology; Humans; Molecular Dynamics Simulation; Somatic Hypermutation, Immunoglobulin
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2016.06.012

Antibody somatic hypermutation (SHM) and affinity maturation enhance antigen recognition by modifying antibody paratope structure to improve its complementarity with the target epitope. SHM-induced changes in paratope dynamics may also contribute to antibody maturation, but direct evidence of this is limited. Here, we examine two classes of HIV-1 broadly neutralizing antibodies (bNAbs) for SHM-induced changes in structure and dynamics, and delineate the effects of these changes on interactions with the HIV-1 envelope glycoprotein (Env). In combination with new and existing structures of unmutated and affinity matured antibody Fab fragments, we used hydrogen/deuterium exchange with mass spectrometry to directly measure Fab structural dynamics. Changes in antibody structure and dynamics were positioned to improve complementarity with Env, with changes in dynamics primarily observed at the paratope peripheries. We conclude that SHM optimizes paratope complementarity to conserved HIV-1 epitopes and restricts the mobility of paratope-peripheral residues to minimize clashes with variable features on HIV-1 Env. [Display omitted] •X-ray crystallography and HDX-MS reveal SHM-induced changes in HIV-1 bNAbs•HDX-MS revealed changes in bNAb dynamics not apparent in crystal structures•Dynamics of sites peripheral to paratopes are tuned during SHM in two bNAb families•SHM changes bNAb structure and dynamics to improve complementarity with HIV-1 Env Hydrogen/deuterium-exchange mass spectrometry and X-ray crystallography were combined to study the impact of somatic hypermutation (SHM) on HIV-1 broadly neutralizing antibody structure and dynamics. SHM-induced stabilization and structural changes improve epitope complementarity and may minimize clashes with dynamic glycans on HIV-1 Env.