PROTEIN-FOLDING - THE ENDGAME

The last stage of protein folding, the ''endgame,'' involves the order ing of amino acid side-chains into a well defined and closely packed c onfiguration. We review a number of topics related to this process. We first describe how the observed packing in protein crystal structures is measured. Such measurements show that the protein interior is pack ed exceptionally tightly, more so than the protein surface or surround ing solvent and even more efficiently than crystals of simple organic molecules. In vitro protein folding experiments also show that the pro tein is close-packed in solution and that the tight packing and interc alation of sidechains is a final and essential step in the folding pat hway. These experimental observations, in turn, suggest that a folded protein structure can be described as a kind of three-dimensional jigs aw puzzle and that predicting side-chain packing is possible in the se nse of solving this puzzle. The major difficulty that must be overcome in predicting side-chain packing is a combinatorial ''explosion'' in the number of possible configurations. There has been much recent prog ress towards overcoming this problem, and we survey a variety of the a pproaches. These approaches differ principally in whether they use ab initio (physical) or more knowledge-based methods, how they divide up and search conformational space, and how they evaluate candidate confi gurations (using scoring functions). The accuracy of side-chain predic tion depends crucially on the (assumed) positioning of the main-chain. Methods for predicting main-chain conformation are, in a sense, not a s developed as that for side-chains. We conclude by surveying these me thods. As with side-chain prediction, there are a great variety of app roaches, which differ in how they divide up and search space and in ho w they score candidate conformations.