Background: Protein volumes change very little on folding at low pressure, but at high pressure the unfolded state is more compact. So far, the molecular origins of this behaviour have not been explained: it is the opposite of that expected from the model of the hydrophobic effect based on the transfer of non-polar solutes from water to organic solvent.
Results: We redetermined the mean volumes occupied by residues in the interior of proteins. The new residue volumes are smaller than those given by previous calculations which were based on much more limited data. They show that the packing density in protein interiors is exceptionally high. Comparison of the volumes that residues occupy in proteins with those they occupy in solution shows that aliphatic groups have smaller volumes in protein interiors than in solution, while peptide and charged groups have larger volumes. The cancellation of these volume changes is the reason that the net change on folding is very small.
Conclusions: The exceptionally high density of the protein interior shown here implies that packing forces play a more important role in protein stability than has been believed hitherto.