Internal packing and protein structural classes.

Protein folding is one of the most important and intriguing of the unsolved problems at the interface between chemistry and biology. The ability of polypeptide chains to fold into unique compact conformations with a vast array of biological functions is rare, if not unique, among high polymers. At this time there is no reason to believe that the chemical interactions currently recognized in small molecules are not directly applicable to proteins, and that the types of these interactions represent the full range that needs to be considered. Of course, the large size of macromolecules and the covalent connectivity will change the relative importance of the various interactions. Some effects barely detectable in small molecules may become dominant in large ones. Of particular interest in the protein folding problem is the observation that similar chain conformations may be seen for a whole series of amino acid sequences that may show little or no sequence homology. The central issue is: "What is the three-dimensional code?" Drexler (1981) has suggested that it may be useful to express the folding problem in inverted form. Rather than ask the usual question, "What is the tertiary structure of a polypeptide chain of specified sequence?", ask the reverse, "What is the full list of sequences compatible with a given structure?" Pabo (1983) has pointed out that the elaboration of this suggestion may be useful for experiments in protein design as well as providing an approach to the folding problem. Although an answer to Drexler's second question would not remove the need for an answer to the first, it might provide some useful insights. We are attempting to develop an algorithm that will provide a list of sequences that are compatible with a given structure. The list is called a tertiary template for the target structure. This phrase was introduced by Blundell and Sternberg (1985), and our use is a generalization of their definition. Our focus in the development of the algorithm has been a long-standing interest in intramolecular packing as a characteristic of proteins. Although this parameter can be evaluated in known structures (Richards 1974), its predictive use in the folding problem has remained elusive, even though it should play a major role. The use of packing considerations in the development of the templates is described below.