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FOLDING THE SHEETS: USING COMPUTATIONAL METHODS TO PREDICT THE STRUCTURE OF PROTEINS 266 To complete this calculation, a PDP 11/70 filling an entire machine room used to work for 48 hours. Today, a laptop computer can complete this same calculation in much less than one hour. An algorithm with a tree architecture can be used to generate these structures. Fortunately, many of the possible structures violate steric constraints (that is, parts of the molecule collide) or disrupt the connectivity of the chain (that is, the interhelix portion of the protein chain cannot stretch from the end of one helix to the start of the next helix), and so large branches of the "tree" can be removed from further consideration. Remarkably, only 20 plausible structures are obtained. Using the additional information that myoglobin contains an iron-bearing heme group, the list can be winnowed: only 2 of the 20 structures could use two histidines to chelate an iron atom surrounded by a heme ring in a sterically reasonable way. As it happens, these 2 structures are extremely similar (rootmean-square displacement (rmsd) between Cα atoms = 0.7 à ) and resemble the crystal structure of myoglobin (rmsd = 4.4 à ). Presumably, detailed energy calculations could be used to refine these structures. To date, the radius of convergence of existing molecular dynamics algorithms is too small to close the 4- à gap between these approximate structures and the X-ray structure. CONCLUSION The protein folding problem is enormously important to biologists. Sequences for exciting new proteins are relatively easy to determine. Structural data for these molecules are much more difficult to obtain. Yet proteins contain a structural blueprint within their sequence. The computational challenge to unravel this blueprint is great. This chapter has highlighted the important problems in this field and identified fertile territory for new investigations. ACKNOWLEDGMENTS This work was supported by grants from the National Institutes of Health, the Searle Scholars Program, and the Advanced Research Projects Agency.
