Probing the “Dark Matter” of Protein Fold Space William R. Taylor, Vijayalakshmi Chelliah, Siv Midtun Hollup, James T. MacDonald, Inge Jonassen  Structure  Volume 17, Issue 9, Pages 1244-1252 (September 2009) DOI: 10.1016/j.str.2009.07.012 Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 1 Examples of Models with a Known and Novel Fold Two α-carbon-based models are shown with α helices colored red and β strands green. Fold a is found in 29 known structures whereas fold b corresponds to none. The representation of these folds as topology strings is illustrated in Experimental Procedures (Figure 4) along with their comparison with known structures (Figure 5). Structure 2009 17, 1244-1252DOI: (10.1016/j.str.2009.07.012) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 2 Protein Fold Space around 2trxA The distance between models was expressed as a metric and projected into 3D (see Experimental Procedures for details) for all pairs of folds generated with the thioredoxin starting probe (2trxA). Novel folds appear as small white spheres and known folds as colored spheres with a radius representing the number of proteins found to contain the fold. Red spheres mark those with close topology to the probe structure. The space is visualized as a stereo pair. Structure 2009 17, 1244-1252DOI: (10.1016/j.str.2009.07.012) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 3 Fold-Complexity Measures (A) The distribution of contact order over the known, novel, and native folds. (B) The distribution of topological accessibility over the known and novel folds. Those with more local packing toward the amino-terminal end appear above the diagonal (green line) and simpler folds lie closer to the origin. Structure 2009 17, 1244-1252DOI: (10.1016/j.str.2009.07.012) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 4 Example Topology Strings Two small αβα layer proteins fitting form 1-5-3 (A) (one helix above and three below a five-stranded sheet) and form 2-5-2 (B) are shown as topology diagrams with their corresponding topology strings below. In the topology diagrams, helices are depicted as circles and β strands as triangles. In the topology strings, the three layers of secondary structure (αβα) are designated A (top), B, and C, respectively. Each secondary structure element (SSE) is given a label of three parts indicating orientation (+, −), layer, and position in the layer. The first SSE in each layer is, by definition, at position 0 with others numbered relative to this. In the topology diagram, negative numbers lie to the left and positive numbers to the right. Similarly, in the strings, a positive orientation corresponds to a SSE approaching (“out of the page”) in the diagrams. Structure 2009 17, 1244-1252DOI: (10.1016/j.str.2009.07.012) Copyright © 2009 Elsevier Ltd Terms and Conditions

Figure 5 Example Rmsd-Based Comparisons A model with a known fold (top frames) and one with a novel fold (lower frames) are shown superimposed (as a stereo pair) on the best match obtained to a native protein structure in the PDB. The structural alignment and superposition was calculated by the program SAP and the residues are colored according to their degree of structural correspondence (red = best to blue = none). The match to 1gnvB (top) has a full topological correspondence over the model but with unmatched additional helices in the PDB structure. The match to 1uuyA (lower) has a topological mismatch of strands in the core β sheet, despite having an equally good rmsd fit. (Compare with Figures 1 and 4, which depict the same folds, and see text for discussion). Structure 2009 17, 1244-1252DOI: (10.1016/j.str.2009.07.012) Copyright © 2009 Elsevier Ltd Terms and Conditions