Fig. 1.

A 3D homology model of SP-B that folds in the closed saposin conformation, constructed by templating the primary sequence of the target SP-B protein onto the lowest energy conformers of the experimental NK-lysin (PDB:1NKL), granulysin (PDB:1L9L), saposin-A (PDB:2DOB), saposin-C (PDB:2GTG), and saposin-D (PDB:3BQP) structures. Human SP-B and the saposin family proteins were aligned by sequence similarities using TM-align [15], followed by structural homology templating and refinement using the server-based I-TASSER program [16] (see Introduction to Saposin Family Proteins). This homology-modeled SP-B shows five amphipathic helices organized in two “leafs.” The first leaf includes the N-terminal insertion sequence and helix 1, C-terminal helix 5, and the leucine repeat helix 4 in close apposition, while the second leaf is composed of the AV repeat helix 2 and inner dimer helix 3 joined by the disulfide stabilized bend. This homology model was used to design novel linear peptides (i.e., Mini-B and Super Mini-B) that when oxidized (i.e., disulfide-linked) not only closely simulate the 3D-structure of the leaf containing the N- and C-terminal helices, but also demonstrate high surfactant activities. Alpha helixes are highlighted in red, disulfide linkages are in yellow, bends and disordered backbone conformations are colored in green.