FIGURE 3.

The proposed folding pathway for CRABP I proceeds through an early hydrophobically collapsed intermediate, I₁ (τ= ~250 μs); followed by formation of an intermediate, I₂, which has native topology and a functional ligand-binding cavity (τ= ~100 ms); and then by establishment of a hydrogen-bonding network and specific tertiary interactions to form the native state, N (τ= ~1 s). The proposed hydrophobic collapse involves interactions among a network of residues (schematically indicated by the gray oval). Productive folding is facilitated locally by turns when their formation brings together essential long-range interactions. Note that Turn IV is at the hub of several topology determining long-range interactions (represented by red circles), and its early formation may be key to folding (folding-active). Turn III is also involved in key long-range interactions (colored green), but these are part of the native hydrophobic packing network and by contrast may drive the formation of this turn instead of the reverse. The sequence of Turn III is thus evolutionarily conserved to allow the native structure to form (folding-passive).