Design of single-chain gp41 NHR mimetics. (A) Ribbon representation of the chain topology of the covNHR constructs. The red and blue helices run in parallel to the original NHR gp41 sequence, whereas the green helix is antiparallel. Short linkers colored in yellow connect the helices. (B) Engineered mutations on the surface covNHR constructs are indicated according to the sequence numbering of covNHR3 (SI Appendix, Table S1). Helices have been separated artificially for clarity. Lines connect residues that establish new interhelical stabilizing interactions. Surface mutations for the first generation constructs are colored in orange; groups A, B, and C of the mutations for the second generation constructs are colored in cyan, green, and blue, respectively. (C) Threefold pseudosymmetry of the covNHR molecule topology. Only the backbone atoms have been represented for clarity. Colors are the same as in A. (D) Molecular surface of the three faces of the covNHR3 model. The sticks colored in blue, yellow, and magenta represent the hydrophobic side chains of complementary CHR residues as they would interact on each hydrophobic pocket of the NHR surface.