(A) Heat map of competitive binding data (Sela-Culang et al., 2014) for 12 antibodies directed against the vaccinia virus D8 protein, with the extent of cross-blocking ranging from 0.0 (white, no effect) to 1.0 (black, complete blocking). Colors in all panels refer to the four Ab groups identified by this competition assay (I: purple, II: blue, III: yellow, and IV: red). (B) Heat map of the overlap between ClusPro-generated docks for each pair of Abs, ranging from 60% (white) to 100% (black). (C) Heat map of the average Hausdorff distance between Ag variants designed for each Ab, ranging from 0 (identical mutation sites, black) to 12 (white). (D–F) Ag variants designed to disrupt one Ab from each group (I: JE11, II: CC7.1, III: EE11, IV: LA5) are represented as triangles. Four designs were sufficient to cover all docking models, and the designs overlapped all of the epitope groups. True epitopes are color coded by group on the surface of the antigen; epitopes in group II and III overlapped, and are colored in green. Design residues overlapping the true epitopes are indicated with circles. (E and F) Zoomed views of epitope faces.