Figure 3

Structural changes on Her2 ectodomain upon binding of trastuzumab and/or pertuzumab. To understand the structural changes that occur as a result of the binding of the two antibodies, we analyse the conformational transition/populations using cross 2D-RMSD plots (a plot of RMSD vs RMSD) of the ectodomain of Her2 in the trajectory of the ternary complex of Her2:pertuzumab:trastuzumab and the different apo and binary trajectories. The latter were fitted onto the full receptor structure, except the pertuzumab epitope region, and the rmsd has been calculated for the Cα atoms using the initial structure of the ternary complex simulation as reference. These maps reveal the differences of the various conformations sampled during the simulation with respect to the ternary complex. Different populations of structures are observed in the plots, with structures closest to the conformation adopted for the receptor at the beginning of the ternary simulations shown in blue, to those that are most altered in red (the largest variations are up to approximately 10 Å RMSD). The binding of trastuzumab displaces the conformation of the receptor towards that found in the ternary complex (see plot at the left and density distribution for such a complex). These conformational changes enhance the binding of pertuzumab and thus the affinity of the two antibodies for the receptor is increased, as shown in Table 1, leading to cooperativity.