The native structure of the glycine-rich antifreeze protein from snow flea, sfAFP, its conformational stability and cooperative folding-unfolding transitions represent a challenge for the current understanding and rationalization of protein folding and stability. The hydrophobic effect, the main stabilizing factor of folded structures, is redefined in terms of the solvent-excluded volume associated with the insertion of a given structure in water to arrive at a different molecular mechanism. The need to minimize the solvent-excluded volume in order to maximize the translational entropy gain of water molecules drives protein folding and determines the globular shape of folded structures. The burial of nonpolar side chains from water contact, as emphasized by the sfAFP folded structure, is not a necessary condition. In fact, a large fraction of nonpolar surface is water-accessible in the folded structures of globular proteins. The significant reduction in water accessible surface area upon chain folding is the necessary and fundamental condition, and rationalizes the conformational stability and cooperativity of sfAFP native structure. HIGHLIGHTS ?The stability and folding characteristics of antifreeze protein from snow flea, sfAFP, are challenging. ?The globular shape of sfAFP is not dictated by nonpolar side chains - water contact. ?The balance between the translational entropy of water molecules and the conformational entropy of the chain is important in protein folding. ?The balance between the formation of intramolecular peptide-peptide H-bonds and the breaking of intermolecular peptide-water H-bonds is important in protein folding.
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