The importance of cooperative interactions and a solid-state paradigm to proteins: what Peptide chemists can learn...

Proteins and peptides in solution or in vivo share properties with both liquids and solids. More often than not, they are studied using the liquid paradigm rather than that of a solid. Studies of molecular crystals illustrate how the use of a solid paradigm may change the way that we consider these important molecules. Cooperative interactions, particularly those involving H-bonding, play much more important roles in the solid than in the liquid paradigms, as molecular crystals clearly illustrate. Using the solid rather than the liquid paradigm for proteins and peptides includes these cooperative interactions while application of the liquid paradigm tends to ignore or minimize them. Use of the solid paradigm has important implications for basic principles that are often implied about peptide and protein chemistry, such as the importance of entropy in protein folding and the nature of the hydrophobic effect. Understanding the folded states of peptides and proteins (especially alpha-helices) often requires the solid paradigm, whereas understanding unfolded states does not. Both theoretical and experimental studies of the energetics of protein and peptide folding require comparison to a suitable standard. Our perspective on these energetics depends on the reasonable choice of reference. The use of multiple reference states, particularly that of component amino acids in the gas phase, is proposed.