To investigate the nature of hydrophobic collapse considered to be the
driving force in protein folding, we have simulated aqueous solutions
of two model hydrophobic solutes, methane and isobutylene. Using a na
vel methodology for determining contacts, vie can precisely follow hyd
rophobic aggregation as it proceeds through three stages: dispersed, t
ransition, and collapsed. Theoretical modeling of the cluster formatio
n observed by simulation indicates that this aggregation is cooperativ
e and that the simulations favor the formation of a single cluster mid
way through the transition stage. This defines a minimum solute hydrop
hobic core volume. We compare this with protein hydrophobic core volum
es determined from solved crystal structures. Our analysis shows that
the solute core volume roughly estimates the minimum core size require
d for independent hydrophobic stabilization of a protein and defines a
limiting concentration of nonpolar residues that can cause hydrophobi
c collapse. These results suggest that the physical forces driving agg
regation of hydrophobic molecules in water is indeed responsible for p
rotein folding.