Protein Decoy Assembly Using Short Fragments Under Geometric Constraints R. Kolodny 1 M. Levitt 2 1 Department of Computer Science, Stanford University, Stanford, CA 94305-5126 2 Department of Structural Biology, Stanford University, Stanford, CA 94305-5126 Received 18 July 2002; accepted 23 July 2002 Abstract: A small set of protein fragments can represent adequately all known local protein structure. This set of fragments, along with a construction scheme that assembles these fragments into structures, defines a discrete (relatively small) conformation space, which approximates protein structures accurately. We generate protein decoys by sampling geometrically valid structures from this conformation space, biased by the secondary structure prediction for the protein. Unlike other methods, secondary structure prediction is the only protein-specific information used for generating the decoys. Nevertheless, these decoys are qualitatively similar to those found by others. The method works well for all- proteins, and shows promising results for  and  proteins. © 2003 Wiley Periodicals, Inc. Biopolymers 68: 278 –285, 2003 Keywords: protein decoy assembly; discrete comformation space; geometric constraints INTRODUCTION The structural biology community has long focused on the very hard task of developing algorithms for solving the ab initio protein folding problem— namely, predicting protein structure from sequence. It seems appropriate in a volume dedicated to the mem- ory of Shneior Lifson to recollect Levitt’s first mem- ories of discussing this problem with Lifson. This occurred at the seventh Ciba Foundation Symposium on Polymerization in Biological Systems, which was organized by Ephraim Katzir and held in London in the autumn of 1971. Levitt was in the third year of his Ph.D. and was only there as Aaron Klug had asked him to attend in his place. This meeting was attended by all the big shots of the time and Levitt was com- pletely out of his depth. His paper was on the folding of nucleic acids 1 and in the extensive discussion pe- riod Lifson asked in his provocative way, “Who cares about how a protein folds. It just happens like a leaf falling from a tree.” At the time Levitt was lost for words and had no real answer other than: “Because the problem is there we must tackle it. . ..” Reflecting back, we now understand more about what Lifson meant. He realized earlier than many that protein folding was a very complicated many-body problem dependent on the details of the underlying Correspondence to: M. Levitt; email: Michael.Levitt@stanford. edu Biopolymers, Vol. 68, 278 –285 (2003) © 2003 Wiley Periodicals, Inc. 278