Fig. 6.

A schematic folding route that underlies the folding mechanism of SH3. This study supports a general explanation for the folding mechanism in which the structural collapse is followed by desolvation of the hydrophobic core. The former is dominated by the formation of short-range contacts (a), whereas the latter is controlled by the closure of interacting β sheets (b–d). Replacing valines with threonines in the hydrophobic core region one at a time probes whether SH3 folding dynamics is relevant to a lubricated hydrophobic core. Those valines of interest are represented by colored spheres: V44, purple; V53, green; others, pink. Decreases of folding rates in V44T and V53T can be explained by using this simple diagram: For V44T, removal of favorable contacts to position 44, which is essential to stabilize contacts between β2, β3, and β4 (shown in a yellow block in a) results in shifting the distribution of contact formation toward the RT loop (shown in a cyan block); kinetic traps are observed. For V53T, position 53 is involved with many long-range contacts such that it plays an important role in stabilizing the core and terminal β-sheets in c. Removal of favorable hydrophobic contacts at this position leads to kinetic traps that appear at a later stage (than a V44T), where desolvation of the hydrophobic core becomes relevant.