Protein folding and stability: What can we learn from high pressure?

The relationships between the amino acid sequence of proteins and their str uctural and functional specificity have yet to be elucidated, as do the det erminants for the marginal stability of the folded form of the chain. The m echanisms by which proteins fold and the nature of the rate-determining ste p in folding remain important questions in the folding field. One important aspect of folded proteins that differentiates them from nonbiological poly mers is the compactness of their folded structures. Proteins, in fact, are packed as densely as crystals of small organic compounds. Thus the shape of each amino acid plays an important role in providing maximal contacts and interaction free energy within the specific folded structure. Deeper insigh t into the importance of packing efficiency in defining the form and stabil ity of the folded structure can be gained by probing the volumetric propert ies of proteins. High pressure as a perturbation of protein structure can g ive access to such volumetric information concerning equilibrium or transit ion states in the folding process. The results of pressure denaturation stu dies must be interpreted in the context of other thermodynamic and kinetic data on protein folding in order to construct a global view of the folding process.