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Allosteric Control of Antibody-Prion Recognition through Oxidation of a Disulfide Bond between the CH and CL Chains

Friday, September 16, 2016 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NCI
IMMUNO-1

Authors

  • J Zhao
  • R Nussinov
  • B Ma

Abstract

Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed MD simulations of the complex of Fab and prion-associated peptide in the apo and bound form. We observed that the inter-chain disulfide bond restrains the conformational changes of Fab, especially the loops on the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains and thereby may prevent the prion peptide binding. We further identified several negative and positive correlations of the motions between the peptide and Fab constant domains, which suggested structural cross-talks between the constant domains and the antigen. The cross-talk was influenced by the inter-chain disulfide bond which reduced the number of paths between them. Importantly, network analysis of the complex and its bound water molecules, observed that those water molecules form an integral part of the Fab/peptide complex network and potential allosteric pathways. On-going work focuses on developing strategies aimed to incorporate these new network communication findings – including the associated water molecules - toward the grand challenge of antibody design.

Category: Immunology