SCIENCE/TECHNOLOGY suggests various tests and experiments to check its viability." Physicist Alexander Y. Grosberg of In a technical tour de force, researchers quences. The most favored structure MIT, who specializes in statistical mehave computed for the first time the among the 51,704 structures analyzed chanics of macromolecules, says the thermodynamic energies of all possible is formed (or designed) by 3,794 differ- paper represents "a tremendous computational achievement." However, he structures for model proteins having 27 ent 27-mers. amino acids. Based on those results, The researchers note that the special points out that the group "employed a they propose that the "designability" structures "possess 'proteinlike' sec- very special model for interactions behypothesis of protein folding explains ondary structure and even tertiary tween the amino acids in their compuwhy only a very small subset of possi- symmetries. In addition, they are ther- tational model. For other interactions ble protein configurations is found in modynamically more stable than other the results could have been completely nature. structures. These results suggest that different." Grosberg also questions othThe number of protein sequences protein structures are selected in nature er methodological aspects of the paper, that can be assembled from different because they are readily designed." such as its use in part of two-dimencombinations of the 20 natural amino The researchers believe the concept of sional models to represent threeacids is astronomical—20400 for pro- designability implicitly accounts for dimensional structures and its attempt to relate certain lattice elements to the teins having 400 amino acids, for exam- and includes foldability. ple. A widely accepted hypothesis In a commentary in Science, physicist secondary structures of real proteins. Protein folding theoretician Eugene states that naturally occurring protein Mehran Kardar of Massachusetts Instistructures form from those sequences tute of Technology, who specializes in Shakhnovich of Harvard University, with the highest "foldability"—the condensed matter theory and polymer who helped conceive the foldability hygreatest tendency to form unique and physics, writes: "Although one needs to pothesis, agrees that the paper's comhighly stable native states. be cautious about results obtained from putations are technically impressive. But physicists Hao Li, Robert Helling, small chains, the [data] uncovered so far But he points out that the designability Chao Tang, and Ned Wingreen of NEC suggest that there may be some deep principle was suggested earlier by Research Institute, Princeton, N.J., pre- truth in the designability principle. Like Alexei V. Finkelstein and coworkers at sent an alternative view [Science, 273, most fertile concepts, it immediately the Institute of Protein Research of the Russian Academy of Sciences, Moscow 666 (1996)]. Their study [FEBS Letters, 325, 23 (1993)]. And he uses lattice models, in believes it is misleading to characterize which amino acids ocProtein sequences tend to gravitate the designability principle as an altercupy evenly distributed native to the foldability model. toward certain structures points inside proteins He adds that the NEC Research Inconstrained to the shape Sequences Structures stitute researchers' results may be "an of a cube. The researchartifact of the model, in which they ers evaluated the eneruse only two types of amino acids. If gies of all the structures they used 20 types of amino acids, it that can be formed from is conceivable that the effect [the emerall possible sequences gence of special structures] would composed of 27 units disappear and that for any 3-D struc(27-mers). The energy ture there would be a lot of sequences calculations are based on having this structure as their native simplified interactions in conformation." which amino acids are Wingreen responds: "There really treated as if they were seem to be two groups of amino acids— one of two types, either hydrophobic ones and polar ones. Some polar or hydrophobic. additional work we did here quantified The results show that the extent to which they fall into two some protein structures classes. We just disagree with Shakhnoare more or less designvich that using more letters in the code able than others—that will eliminate special structures." is, that they can be codSchematic mapping of protein sequence to Li says recent work has enabled the ed by a highly variable structure shows that some structures (such as the group to understand how geometric number of different prosecond from top) are "designed" by many features of special structures lead to tein sequences. Some different sequences, whereas other structures are their high designability. Based on these structures are so unfaorphans that don't get adopted by any sequences results, he says, "our prediction would vored that no 27-mer at all. Sequences are represented in this be that even if you go on using addisequences form into simulation as strings of polar (blue) and tional letters, you'd still find the emerthem. But others are hydrophobic (black) amino acids. gence of special structures. We intend "special" structures Courtesy of Hao Li, NEC Research Institute. Adapted with to test this in the near future." permission from Science, copyright 1996 AAAS. that are produced by Stu Borman lots of different se-
Protein folding model focuses on 'designability'
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AUGUST 12,1996 C&EN
