A typical protein would contain a few salt-bridges, several hundred hydrogen bonds and several thousand van der Waals interactions. This is because of several effects which cancel each other out. Hence the overall enthalpy change on folding is small. Shows the ordering of water molecules surrounding a hydrophobic molecule.
Green lines indicate hydrogen bonds.
Hence the driving force of protein folding is thought to be the hydrophobic effect i.e. the hydrophobic side chains aggregate excluding water molecules as the protein folds. The resulting increase in entropy of these water molecules gives rise to a large positive D S causing the D G of folding to be negative i.e. thermodynamically favourable. Note that the entropy of the polypeptide itself decreases on folding which will counteract the increase in D S due to the waters. It was subsequently shown that chemically synthesised ribonuclease A was enzymically active. These results are generally taken as evidence for the thermodynamic hypothesis of folding.