Supplementary Figure 11: Structural modeling comparing the interaction with HER2 of WT pertuzumab with the acid-switched mutant SG at pH 7.4 and 5.8.

(a) Analyses of the contribution of van der Waals (vdW), geometry (Geo), nonpolar hydration free energy (based on the solvent-accessible surface area, or SASA), and continuum electrostatics (Elec) to the differences in binding free energies (ΔΔG) between the SG mutant and WT pertuzumab interacting with HER2 at pH 7.4 and 5.8. (b) Energy decompositions of the Elec interactions shown in (a) for the residues that make the largest energetic contributions to the different binding behavior of WT and SG (HER2 and pertuzumab CDRH2 residues are shown in orange and cyan, respectively), with the most important contributors indicated by boxes. (c,d) The differences in the protonation states (residues His55 and Ser55 of SG and WT, respectively) and conformational states (residue Tyr252 of HER2) between WT pertuzumab and the SG mutant at pH 7.4 (c) and 5.8 (d). The modeled structures of the pertuzumab:HER2 extracellular domain complex are shown, with the pertuzumab VH domain, VL domain and HER2 domain II shown in cyan, light cyan, and orange, respectively. Residues for the SG:HER2 and WT:HER2 complexes are labeled in bold and parentheses, respectively.