We have developed a rapid and completely automatic method for prediction of protein side-chain conformation, applying the simulated annealing algorithm to optimization of side-chain packing (van der Waals) interactions. The method directly attacks the combinatorial problem of simultaneously predicting many residues' conformation, solving in 8 to 12 hours problems for which the systematic search would require over 10(300) central processing unit years. Over a test set of nine proteins ranging in size from 46 to 323 residues, the program's predictions for side-chain atoms had a root-mean-square (r.m.s.) deviation of 1.77 A overall versus the native structures. More importantly, the predictions for core residues were especially accurate, with an r.m.s. value of 1.25 A overall: 80 to 90% of the large hydrophobic side-chains dominating the internal core were correctly predicted, versus 30 to 40% for most current methods. The predictions' main errors were in surface residues poorly constrained by packing and small residues with greater steric freedom and hydrogen bonding interactions, which were not included in the program's potential function. van der Waals interactions appear to be the supreme determinant of the arrangement of side-chains in the core, enforcing a unique allowed packing that in every case so far examined matches the native structure.

No abstract

No abstract

The last stage of protein folding, the "endgame," involves the ordering of amino acid side-chains into a well defined and closely packed configuration. 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 packed exceptionally tightly, more so than the protein surface or surrounding solvent and even more efficiently than crystals of simple organic molecules. In vitro protein folding experiments also show that the protein is close-packed in solution and that the tight packing and intercalation of side-chains is a final and essential step in the folding pathway. These experimental observations, in turn, suggest that a folded protein structure can be described as a kind of three-dimensional jigsaw puzzle and that predicting side-chain packing is possible in the sense 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 progress towards overcoming this problem, and we survey a variety of the approaches. 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 configurations (using scoring functions). The accuracy of side-chain prediction depends crucially on the (assumed) positioning of the main-chain. Methods for predicting main-chain conformation are, in a sense, not as developed as that for side-chains. We conclude by surveying these methods. As with side-chain prediction, there are a great variety of approaches, which differ in how they divide up and search space and in how they score candidate conformations.

No abstract