Model structure of a full-length anti-IgE complexed with IgE (P3384)

Abstract

Abstract Modeling antibody/antigen (Ab/Ag) complexes remains a challenging problem and is important for understanding how proteins associate, which in turn can aid drug design. Recently, we have implemented a method (EMAP) for producing the conformations of Ab/Ag complexes in the widely used molecular dynamics program CHARMM. Here, we apply this method to model the structure of IgE in complex with omalizumab, a humanized IgG1 antibody that has been approved in many countries for treating severe, persistent allergic asthma. First, the EMAP method was calibrated by using it to reproduce 24 nonredundant Ab/Ag complexes whose bound and unbound structures have been solved. It could yield near-native conformations for 22 of the 24 complexes, whereas other docking methods such as ZDOCK yield less near-native conformations. Having validated the EMAP method, it was used to dock full-length models of omalizumab and IgE together. The resulting IgE/omalizumab complex structure provides insights into the relative importance of the residues involved in binding. It also provides a plausible explanation for why omalizumab and IgE do not form large immune complexes.