Specific Residue Interactions Regulate the Binding of Dengue Antigens to Broadly Neutralizing EDE Antibodies.

Abstract

Antibodies binding to antigens present on the dengue virus (DENV) represent the main defense mechanism of the host organism against the pathogen. Among the antibodies elicited by DENV and that bind to DII of protein E, EDE1‐C8 can bind all DENV serotypes. Our analysis reveals the key residues in this interaction as well as structurally conserved hydrogen bonds located at the binding interface. They stabilize the dengue antigen–antibody complex among the EDE1 group of antibodies (Abs). Combining structural alignments with molecular dynamics simulations in the EDE1 Abs, we identified the critical elements that provide a major energetic contribution to the association of antigens from protein E with Abs. We discuss possible molecular insights into the binding mechanism by using a surrogate molecular entity resembling the protein E that forms native salt bridges and hydrogen bonds, including inferences on the light of high‐resolution crystal structures of dengue Fab complexes. Finally, the molecular determinants, the free energy profile, and the binding mechanism provide inspiration for potential strategies in protein engineering to design novel immunogens of protein E against DENV.