Allosteric control of antibody-prion recognition through oxidation of a disulfide bond between the CH and CL chains.

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 molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding. We further identified several negative and positive correlations of 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 communications-including the associated water molecules-toward the grand challenge of antibody design. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

See More