Figure 2

Thermodynamic cycles to study the cooperative binding of Her2 to trastuzumab and pertuzumab. (A) The cycle with the energy estimations calculated from the independent association simulations. (B) The cycle analysed using the conformations of receptor and binary complexes from the co-localized interaction simulations. The energetics for the binary complexes have been obtained from the ternary complex of Her2:pertuzumab:trastuzumab complex, in an attempt to account for the influence of the other antibody when both are co-localized. (C) The cycle representing the gain in energy between the binding of the two antibodies to each other in an isolated system or when co-localized onto the structure of the receptor. The ectodomain of Her2 has been coloured in green, while trastuzumab and pertuzumab are represented in black and orange, respectively. The differences in free energy binding estimated for every system are shown. The computations were for the following schemes: A) her2-trastuzumab < -her2+ trastuzumab; her2-trast-pert < -her2-trast + pertuzumab her2-trast + pertuzumab < -her2+ trastuzumab + pertuzumab her2-pertuzumab < -her2+ pertuzumab; her2-trast-pert < -her2-pert + trastuzumab. B) her2-trastuzumab (extracted from her2:pert:trast) < -her2+ trastuzumab; her2-trast-pert < -her2-trast (extracted from her2-pert:trast) + pertuzumab her2-pertuzumab (extracted from her2:pert:trast) < -her2+ pertuzumab; her2-trast-pert < -her2-pert (extracted from her2-pert:trast) + trastuzumab. C) Abs (extracted from her2:pert:trast) < -pertuzumab + trastuzumab; Abs < -pertuzumab + trastuzumab.