Fig. 2. Proposed unassisted folding model for a membrane β-barrel protein.

(a) A nascent eight-stranded OMP rapidly adsorb to the cis surface (green) of the lipid bilayer, where hydrophobic lipid-facing side chains begin to penetrate into the membrane and β-strands assume a cloverleaf-like circular arrangement according to their relative position in the folded protein. (b) β-hairpins begin to form as the trans ends of the TM β-strands, oriented toward the center of the cloverleaf, plunge into the lipid phase. (c) Hydrogen bonds form between neighboring β-hairpins as they enter the membrane, stabilizing the native fold in concert with membrane insertion. The highlighted dashed line indicates the proposed path of the leading (trans) ends of the β-strands.