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The Evolution of Protein Folds Spencer Bliven Department of Bioinformatics University of California San Diego Andreas Prlić San Diego Supercomputer Center University of California San Diego Philip Bourne Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego Methods 1.Identification of domain and subdomain architecture a. Use SCOP domains where available, or calculate using the Protein Domain Parser (PDP) algorithm b.Detect symmetry using CE-Symm (manuscript in preparation) c.Detect circular permutations using CE-CP (Shindyalov, 2000; Prlic, 2010) 2.All-vs-all structural similarity calculation a. Filter representatives to 40% sequence identity b.Use FATCAT algorithm (Ye and Godzik, 2003) to compare all protein domains from the Protein Data Bank (nearly 1 billion alignments, accessible from http://www.pdb.org ) 3.Network analysis a. Filter out low-scoring structural alignments (TMScore0.5, Length25, Coverage60%) b.Map functional properties onto nodes: SCOP/CATH classification, GO terms, symmetry order, ligand information, etc. 4.Phylogenetic analysis (planned) Future work will center on quantifying the prevalence of subdomain rearrangement by integrating evolutionary data with the structural comparison data. The nature of protein fold space is hotly debated. Do the protein folds observed in nature fall into clean, discrete clusters, or is fold space more accurately modeled as a vast continuum, of which only a small sample of proteins has yet been observed? Previous efforts to answer this question have focused on geometric spaces (PCA, multidimensional scaling, locally linear embedding) or network models (conformational space networks) (Chodera, 2011). While such schemes may facilitate protein comparison and classification, the choice of a mathematical framework for fold space is arbitrary without a connection to concrete biological processes. To accurately capture the true relationships between protein folds, a model must consider the evolutionary history of those folds. Here we present a high-level model of protein evolution, which focuses on mutations that preserve the global 3D structure of proteins. We hypothesize that the combination of subtle local changes (e.g. PTMs) and large, but structure-preserving, rearrangements (e.g. duplications) can account for both the continuity of intermediate structures within protein folds and the evolution of seemingly novel folds. Our model categorizes known biological mutation processes, such as DNA replication errors and crossover errors, and places them in a simple theoretical framework. To test this model, we present evidence from the analysis of a recent systematic comparison of all protein domains from the Protein Data Bank (PDB). We also show that the model is consistent with existing evolutionary models for gene duplication, circular permuted proteins, and proteins with internal symmetry. Future work will focus on explicitly determining evolutionary events relating distantly homologous folds. Abstract Poster first presented at the 20th Annual International Conference on Intelligent Systems for Molecular Biology (2012). Funded in association with the Protein Data Bank. The presentation of this work was made possible by a Travel Fellowship awarded by ISCB with grant funds obtained from the NIH NIMGS-National Institute of General Medical Sciences. This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA. Model for the Evolution of New Folds Given these observations, we hypothesize that structure-preserving rearrangements are a major mechanism for the evolution of new protein folds. To test this, we classify mutations into the following categories: 1.Gene fusion A gene fusion occurs when two previously independent protein sequences are joined to create a single peptide product. This includes duplications, where the source sequence are identical, as well as the creation of chimeric proteins. To preserve function, the source proteins should either interact or form independently folding domains; other fusions are likely to be selected against. 2.Gene fission A single peptide may split into two independently transcribed peptides. While a fission may be accompanied by the loss of the protein-protein interface, fissions which maintain the global structure of the protein are likely to be selected for. 3.Gain of protein-protein interface The evolution of a new protein-protein interface results in a new quaternary structure. This may be either a heteromer, as shown in the diagram, or a homomer. 4.Loss of protein-protein interface Protein-protein interfaces may also be lost. This may occur in conjunction with fission. 5.Non-architectural mutations Any mutation which does not alter the number of domains, binding, or connectivity is termed a non-architectural mutation. This includes insertions, deletions, and substitutions of amino acids or even whole secondary structures. 6.Order-disorder transitions For completeness, order-disorder transitions are included as a possible source of novel folds. However, such transitions are extremely difficult to detect, and are indistinguishable from primordial folds by the methods used in this study. Principles of Protein Evolution 1. Global structure is conserved in many significant rearrangements 2. Domains and subdomains are reused for many functions (a) The TorD chaperon from Shewanella massilia (1N1C) is a dimer, but instead of each chain folding into a compact domain, each chain contributes to the structure or each domain. (b) The DmsD protein from Salmonella typhimurium (1S9U) has a very similar structure and has 20% sequence identity, but forms a monomer (Sippl, 2009). (a) (b) Domain Swapping Circular Permutation Symmetry (a) (b) (c) (a) Alignment of Regulatory Protein A from Human papillomavirus (1A7G) with AppA BLUF domain from Rhodobacter sphaeroides (2IYG). The two structures are related by a circular permutation, as can be seen from the rainbow coloring in (b) and (c) The symmetric protein FGF-1 (3JUT), colored to highlight the 3-fold symmetry. Evidence suggests that ß-trefoils may have evolved from a trimeric precursor (Lee, 2011). GTP binding regulator from Thermotoga maritima [1VR8] consists of two αβββ motifs, colored orange and yellow. The half-glyoxalase query motif (cyan) is aligned for comparison. Structure of glyoxalase I from E. coli [3HDP]. Colors show the two-fold symmetry of the protein around its nickel-binding site. Dimer form of glyoxalase I [1F9Z], colored by chain. Relative to 3HDP, the symmetric motifs are swapped between chains. 1,2dihydroxynaphthalene dioxygenase [2EHZ] from Pseudomonas (orange/grey) consists of four copies of the half- glyoxalase motif (cyan). Iron is bound at the active site. Fusion Fission Loss of interface Gain of interface Conclusion We aim to provide a model for analyzing protein fold space based not on geometric properties, but on evolutionary relationships. This approach avoids the dichotomy of "continuous" and "discrete". Our model is derived from the observation that many proteins which are currently classified as belonging to separate folds can be decomposed into subdomains which appear in many different subdomain architectures. The evolution of protein symmetry is a prime example of this phenomenon. Proteins may be symmetric at the level of quaternary structure, tertiary structure, or both. Significant homology can often be detected between the repeated subunits of symmetric proteins, suggesting that symmetry evolves by duplication and fusion events. These events preserve the protein-protein interaction interfaces and the global structure of the protein, providing a plausible pathway for radical fold change without non- functional intermediates. Likewise, the currently accepted models for the evolution of circular permutations can be couched as a special case of the model presented here (Weiner, 2006). To investigate the evolution of protein folds as broadly as possible, an extensive all-vs-all comparison of domains from the Protein Databank was conducted. This consisted of nearly one billion pairwise alignments, and was performed on the Open Science Grid distributed cluster. This wealth of data allows the clustering of potentially homologous domains. Research is ongoing to incorporate evolutionary information into this network, with the ultimate goal of quantifying the prevalence of each mechanism for fold evolution. Chodera & Pande (2011) PNAS. vol.108(32) pp. 12969–12970 Lee & Blaber (2011) PNAS, vol.108 (1) pp. 126–130 Prlic et al. (2010) Bioinformatics. vol. 26 (23) pp. 2983-2985 Shindyalov and Bourne (2000) Proteins. vol. 38 (3) pp. 247-60 Sippl (2009) Curr Opin Struct Biol. vol.19 (3) pp. 312-20 Thornalley (1993) Mol. Aspects Med. 14 (4) pp. 287–371 Ye and Godzik (2003). Bioinformatics. vol. 19(Suppl 2), pp. ii246–55. Weiner & Bornberg-Bauer (2006) Mol. Biol. Evol. vol. 23(4) pp. 734–743 (Left) Structural similarities between domains of transmembrane proteins, as classified by the Transporter Classification Database (TCDB). A moderate threshold of 0.5 was used, leaving the network fairly sparse. The nodes are colored according to their TCDB (Right) Enlargement of the boxed section of the graph, with 3D structures overlaid. All structures are similar to the Rossmann fold, but several are classified in different SCOP folds (e.g. PTS system IIB component-like (d1iiba_)). A wide diversity of TCDB functions are annotated to the PDP:2AEFAa PDP:3IPRAa PDP:2FN9Ab d1iiba_ PDP:3L9WAa d1pdoa_ PDP:3A1DAa d1shux_ EAa PDP:2FN9Aa PDP:2VOYIa PDP: PDP:3I PDP:2Q d1id1a_ d2hmva1 PDP:2WI8Aa PDP:3QJGAa PDP:3P2YAb PDP:2FEWBa PDP:3RBZAb d1vkra_ PDP:2VQ3Aa 0.5 0.64 0.52 0.57 0.54 0.53 0.53 0.58 0.65 0.66 0.75 0.65 0.52 0.53 0.63 0.57 0.55 0.75 0.58 0.6 0.56 0.64 0.73 0.73 0.61 0.66 0.71 0.59 0.58 0.77 0.5 0.64 0.52 0.5 0.51 0.54 0.6 0.53 0.67 0.6 0.7 0.67 0.53 0.51 0.66 0.56 0.61 0.6 0.65 0.52 0.54 0.58 0.7 0.52 0.69 0.77 0.57 0.56 0.53 0.5 0.76 0.54 0.61 0.65 0.56 0.59 0.55 0.57 0.61 0.55 0.69 0.5 0.55 0.67 0.65 0.54 0.58 0.64 0.5 0.53 0.68 0.56 0.51 0.5 0.52 0.61 0.53 0.55 0.62 0.62 0.58 0.61 0.5 0.67 0.8 0.58 0.84 0.69 0.69 0.68 0.52 0.6 0.56 0.55 0.6 0.6 0.55 0.55 0.55 0.56 0.52 0.58 0.55 0.51 0.67 0.55 0.68 0.62 0.58 0.7 0.67 0.56 0.64 0.65 0.55 0.64 0.61 0.57 0.5 0.67 0.62 0.72 0.51 0.64 0.53 0.69 0.58 0.62 0.56 0.56 0.5 0.5 0.6 0.51 0.53 0.84 0.51 0.78 0.7 0.6 0.78 0.54 0.52 0.5 0.53 0.5 0.54 0.52 0.62 0.62 0.56 0.55 0.55 0.69 0.61 0.6 0.72 0.81 0.58 0.87 0.58 0.78 0.61 0.52 0.85 0.57 0.53 0.53 0.74 0.55 0.79 0.81 0.84 0.67 0.68 0.61 0.67 0.73 0.59 0.77 0.57 0.59 0.81 0.88 0.5 0.57 0.57 0.6 0.65 0.71 0.59 0.5 0.57 0.54 0.62 0.53 0.66 0.65 0.57 0.74 0.51 0.58 0.59 0.69 0.7 0.76 0.72 0.8 0.87 0.53 0.83 0.73 0.7 0.62 0.76 0.66 0.67 0.7 0.58 0.6 0.6 0.69 0.78 0.66 0.53 0.54 0.67 0.53 0.62 0.71 0.53 0.79 0.56 0.52 0.58 0.66 0.75 0.71 0.74 0.69 0.62 0.68 0.63 0.55 0.55 0.65 0.55 0.68 0.74 0.66 0.68 0.6 0.52 0.69 0.6 0.72 0.83 0.59 0.91 0.6 0.74 0.52 0.59 0.71 0.76 0.73 0.54 0.52 0.94 0.52 0.54 0.73 0.53 0.53 0.51 0.5 0.54 0.64 0.62 0.82 0.59 0.71 0.9 0.66 0.51 0.84 0.73 0.51 0.52 0.72 0.59 0.56 0.53 0.61 0.7 0.67 0.52 0.63 0.82 0.53 0.61 0.55 0.5 0.93 0.53 0.55 0.5 0.59 0.52 0.62 0.52 0.5 0.56 0.53 0.68 0.56 0.56 0.61 0.57 0.5 0.55 0.54 0.65 0.61 0.56 0.5 0.69 0.54 0.62 0.56 0.53 0.62 0.57 0.69 0.65 0.77 0.58 0.66 0.67 0.65 0.77 0.79 0.77 0.76 0.61 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0.61 0.77 0.59 0.52 0.52 0.52 0.54 0.5 0.58 0.57 0.64 0.51 0.52 0.54 0.59 0.55 0.53 0.53 0.52 0.64 0.55 0.6 0.55 0.54 0.54 0.69 0.52 0.78 0.5 0.63 0.56 0.83 0.66 0.85 0.61 0.5 0.62 0.76 0.53 0.5 0.52 0.51 0.51 0.5 0.51 0.53 0.84 0.98 0.5 0.64 0.55 0.99 0.88 0.88 0.71 0.75 0.75 0.87 0.82 0.81 0.51 0.55 0.64 0.5 0.55 0.51 0.93 0.52 0.54 0.52 0.54 0.84 0.92 0.87 0.8 0.82 0.91 0.74 0.75 0.71 0.84 0.8 0.75 0.52 0.6 0.72 0.73 0.7 0.52 0.6 0.56 0.67 0.81 0.59 0.75 0.69 0.56 0.81 0.85 0.83 0.96 0.96 0.96 0.96 0.57 0.56 0.93 0.83 0.97 0.82 0.92 0.89 0.61 0.77 0.63 0.64 0.72 0.73 0.64 0.57 0.71 0.72 0.59 0.67 0.69 0.56 0.7 0.69 0.55 0.69 0.57 0.7 0.69 0.77 0.57 0.61 0.9 0.53 0.95 0.63 0.84 0.91 0.78 0.89 0.87 0.81 0.73 0.73 0.92 0.76 0.91 0.75 0.73 0.9 0.76 0.52 0.53 0.7 0.68 0.7 0.54 0.94 0.57 0.93 0.84 0.93 0.89 0.89 0.98 0.81 0.98 0.63 0.62 0.94 0.6 0.54 0.53 0.5 0.53 0.52 0.6 0.52 0.61 0.6 0.53 0.56 0.52 0.5 0.53 0.56 0.6 0.5 0.5 0.51 0.54 0.57 0.81 0.79 0.8 0.52 0.5 0.54 0.51 0.54 0.5 0.5 0.57 0.5 0.55 0.54 0.57 0.5 0.52 0.52 0.56 0.57 0.5 0.51 0.55 0.56 0.54 0.51 0.97 0.5 0.96 0.5 0.55 0.56 0.58 0.54 0.6 0.55 0.54 0.5 0.53 0.55 0.57 0.54 0.55 0.54 0.56 0.52 0.59 0.98 0.53 0.51 0.56 0.53 0.54 0.6 0.98 0.51 0.54 0.53 0.51 0.53 0.55 0.57 0.55 0.55 0.54 0.55 0.53 0.58 0.98 0.54 0.77 0.77 0.67 0.64 0.58 0.66 0.54 0.58 0.56 0.69 0.66 0.57 0.68 0.51 0.5 0.56 0.58 0.59 0.5 0.52 0.84 0.57 0.5 0.56 0.54 0.56 0.53 0.51 0.56 0.56 0.53 0.57 0.53 0.56 0.51 0.52 0.56 0.6 0.51 0.5 0.57 0.52 0.56 0.53 0.52 0.57 0.57 0.51 0.66 0.72 0.53 0.58 0.82 0.82 0.98 0.53 0.54 0.54 0.5 0.55 0.81 0.67 0.92 0.54 0.65 0.8 0.72 0.65 0.59 0.64 0.6 0.53 0.58 0.53 0.5 0.58 0.54 0.52 0.53 0.53 0.5 0.54 0.5 0.6 0.78 0.54 0.55 0.68 0.87 0.82 0.79 0.83 0.79 0.8 0.84 0.6 0.55 0.67 0.79 0.85 0.85 0.71 0.89 0.61 0.8 0.7 0.63 0.64 0.81 0.8 0.75 0.53 0.92 0.65 0.81 0.78 0.6 0.85 0.57 0.85 0.69 0.66 0.58 0.95 0.9 0.75 0.86 0.54 0.83 0.84 0.59 0.54 0.8 0.64 0.62 0.78 0.78 0.54 0.93 0.76 0.63 0.84 0.54 0.82 0.66 0.66 0.58 0.9 0.75 0.81 0.8 0.7 0.56 0.86 0.61 0.56 0.76 0.8 0.59 0.82 0.8 0.56 0.86 0.59 0.85 0.67 0.67 0.58 0.89 0.72 0.81 0.85 0.58 0.56 0.52 0.63 0.74 0.7 0.77 0.62 0.79 0.57 0.82 0.65 0.7 0.66 0.53 0.82 0.73 0.82 0.54 0.77 0.6 0.6 0.87 0.81 0.63 0.73 0.64 0.76 0.66 0.76 0.65 0.62 0.63 0.75 0.67 0.74 0.6 0.76 0.56 0.6 0.59 0.78 0.61 0.66 0.6 0.74 0.65 0.74 0.67 0.6 0.62 0.71 0.65 0.71 0.56 0.72 0.52 0.63 0.73 0.62 0.78 0.66 0.5 0.77 0.58 0.64 0.73 0.59 0.84 0.67 0.68 0.56 0.77 0.59 0.61 0.58 0.97 0.52 0.58 0.76 0.59 0.71 0.83 0.52 0.79 0.57 0.56 0.78 0.65 0.67 0.54 0.78 0.69 0.8 0.55 0.6 0.69 0.64 0.86 0.69 0.69 0.54 0.65 0.81 0.53 0.73 0.88 0.76 0.65 0.65 0.53 0.8 0.53 0.58 0.64 0.55 0.65 0.64 0.54 0.72 0.82 0.72 0.53 0.53 0.55 0.57 0.77 0.63 0.59 0.52 0.66 0.76 0.53 0.67 0.69 0.56 0.55 0.58 0.62 0.53 0.52 0.55 0.6 0.54 0.55 0.97 0.54 0.54 0.66 0.57 0.57 0.52 0.59 0.58 0.54 0.64 0.58 0.5 0.61 0.56 0.56 0.57 0.58 0.54 0.66 0.55 0.69 0.68 0.58 0.63 0.83 0.54 0.5 0.56 0.68 0.7 0.67 0.59 0.61 0.51 0.65 0.54 0.63 0.59 0.58 0.51 0.63 0.52 0.62 0.64 0.61 0.57 0.51 0.57 0.66 0.67 0.69 0.67 0.6 0.69 0.68 0.63 0.63 0.77 0.62 0.64 0.76 0.88 0.76 0.78 0.75 0.9 0.75 0.73 0.84 0.82 0.88 0.84 0.83 0.81 0.74 0.68 0.66 0.63 0.55 0.68 0.61 0.59 0.82 0.83 0.95 0.74 0.65 0.84 0.76 0.53 0.96 0.87 0.96 0.54 0.89 0.89 0.81 0.85 0.74 0.69 0.75 0.7 0.69 0.59 0.56 0.6 0.52 0.5 0.52 0.67 0.53 0.81 0.69 0.9 0.84 0.92 0.66 0.9 0.8 0.68 0.69 0.67 0.93 0.81 0.6 0.84 0.58 0.63 0.62 0.99 0.56 0.76 0.76 0.66 0.68 0.75 0.86 0.74 0.64 0.65 0.52 0.51 0.54 0.68 0.61 0.63 0.58 0.55 0.79 0.54 0.98 0.62 0.55 0.51 0.5 0.59 0.52 0.52 0.54 0.52 0.56 0.52 0.6 0.92 0.83 0.61 0.78 0.56 0.62 0.85 0.5 0.5 0.51 0.5 0.64 0.52 0.63 0.53 0.55 0.52 0.86 0.84 0.8 0.61 0.87 0.87 0.53 0.53 0.54 0.53 0.5 0.87 0.76 0.98 0.97 0.65 0.58 0.62 0.68 0.63 0.66 0.63 0.71 0.6 0.64 0.62 0.62 0.83 0.54 0.69 0.78 0.89 0.7 0.69 0.71 0.71 0.89 0.88 0.7 0.69 0.89 0.58 0.72 0.57 0.68 0.61 0.65 0.6 0.67 0.62 0.6 0.5 0.91 0.89 0.92 0.69 0.9 0.71 0.93 0.67 0.85 0.92 0.68 0.86 0.71 0.9 0.82 0.67 0.7 0.89 0.9 0.7 0.87 0.68 0.89 0.66 0.68 0.89 0.72 0.86 0.71 0.82 0.73 0.88 0.72 0.67 0.85 0.7 0.68 0.69 0.71 0.94 0.87 0.83 0.73 0.74 0.87 0.88 0.68 0.62 0.92 0.7 0.76 0.69 0.9 0.77 0.94 0.71 0.72 0.69 0.77 0.68 0.85 0.8 0.68 0.69 0.92 0.79 0.81 0.8 0.84 0.8 0.89 0.87 0.83 0.81 0.89 0.88 0.83 0.85 0.78 0.84 0.78 0.8 0.85 0.81 0.8 0.73 0.83 0.78 0.77 0.81 0.82 0.84 0.87 0.77 0.83 0.69 0.89 0.5 0.86 0.87 0.73 0.8 0.84 0.88 0.71 0.79 0.83 0.72 0.76 0.85 0.89 0.68 0.68 0.84 0.5 0.76 0.76 0.93 0.65 0.57 0.63 0.52 0.65 0.7 0.97 0.65 0.7 0.54 0.7 0.67 0.56 0.6 0.5 0.51 0.53 0.57 0.7 0.53 0.51 0.52 0.54 0.5 0.52 0.53 0.5 0.54 0.54 0.52 0.53 0.54 0.55 0.55 0.55 0.53 0.51 0.62 0.54 0.54 0.5 0.53 0.51 0.52 0.53 0.51 0.52 0.54 0.61 0.62 0.66 0.52 0.59 0.61 0.52 0.55 0.53 0.52 0.61 0.55 0.55 0.53 0.53 0.56 0.53 0.53 0.63 0.64 0.62 0.57 0.6 0.57 0.62 0.57 0.58 0.59 0.57 0.56 0.59 0.5 0.53 0.64 0.62 0.51 0.59 0.5 0.59 0.59 0.57 0.55 0.62 0.6 0.57 0.58 0.59 0.53 0.79 0.79 0.6 0.55 0.55 0.58 0.55 0.53 0.53 0.54 0.6 0.64 0.53 0.56 0.53 0.55 0.68 0.55 0.54 0.84 0.75 0.83 0.67 0.69 0.71 0.79 0.6 0.69 0.9 0.74 0.75 0.72 0.77 0.89 0.73 0.76 0.89 0.72 0.65 0.58 0.75 0.72 0.73 0.88 0.72 0.73 0.78 0.5 0.52 0.51 0.5 0.51 0.82 0.72 0.79 0.51 0.85 0.51 0.54 0.56 0.54 0.6 0.52 0.92 0.53 0.53 0.55 0.51 0.51 0.99 0.51 0.51 0.56 0.5 0.51 0.55 0.54 0.53 0.54 0.78 0.55 0.56 0.61 0.69 0.57 0.78 0.6 0.5 0.54 0.54 0.52 0.57 0.67 0.57 0.59 0.58 0.66 0.5 0.58 0.58 0.6 0.67 0.7 0.63 0.55 0.67 0.7 0.66 0.51 0.69 0.65 0.5 0.72 0.55 0.51 0.56 0.5 0.99 0.53 0.51 0.51 0.61 0.52 0.89 0.64 0.58 0.61 0.59 0.52 0.52 0.63 0.5 0.55 0.53 0.61 0.61 0.6 0.68 0.61 0.5 0.62 0.62 0.61 0.55 0.51 0.54 0.51 0.55 0.57 0.58 0.78 0.51 0.8 0.73 0.71 0.73 0.75 0.59 0.81 0.81 0.53 0.62 0.83 0.86 0.56 0.95 0.72 0.81 0.7 0.65 0.97 0.62 0.66 0.93 0.56 0.8 0.67 0.83 0.65 0.62 0.82 0.66 0.69 0.65 0.68 0.66 0.57 0.67 0.7 0.54 0.64 0.63 0.56 0.56 0.54 0.61 0.51 0.65 0.62 0.89 0.55 0.6 0.65 0.62 0.54 0.5 0.52 0.53 0.59 0.54 0.55 0.84 0.7 0.81 0.85 0.72 0.54 0.81 0.77 0.51 0.51 0.95 0.72 0.57 0.57 0.7 0.56 0.51 0.77 0.64 0.64 0.61 0.8 0.74 0.77 0.53 0.53 0.6 0.71 0.72 0.68 0.83 0.64 0.63 0.62 0.5 0.66 0.69 0.7 0.57 0.69 0.98 0.87 0.82 0.68 0.98 0.87 0.71 0.75 0.59 0.68 0.79 0.59 0.76 0.53 0.97 0.81 0.69 0.85 0.86 0.88 0.76 0.85 0.8 0.76 0.69 0.72 0.83 0.88 0.83 0.77 0.76 0.7 0.74 0.73 0.65 0.74 0.51 0.79 0.61 0.77 0.86 0.85 0.78 0.82 0.51 0.56 0.72 0.71 0.94 0.61 0.92 0.59 0.51 0.56 0.56 0.68 0.72 0.55 0.99 0.5 0.55 0.51 0.5 0.5 0.66 0.58 0.56 0.75 0.7 0.53 0.56 0.57 0.93 0.85 0.95 0.81 0.91 0.92 0.75 0.88 0.5 0.55 0.5 0.66 0.61 0.66 0.6 0.83 0.65 0.72 0.85 0.77 0.76 0.88 0.81 0.73 0.52 0.54 0.51 0.88 0.99 0.5 0.81 0.61 0.83 0.84 0.81 0.96 0.91 0.57 0.95 0.61 0.81 0.94 0.78 0.61 0.54 0.81 0.73 0.77 0.64 0.65 0.63 0.62 0.65 0.58 0.7 0.98 0.83 0.58 0.68 0.82 0.66 0.72 0.73 0.83 0.61 0.84 0.64 0.95 0.64 0.56 0.55 0.95 0.74 0.72 0.73 0.88 0.82 0.77 0.9 0.97 0.94 0.94 0.91 0.98 0.81 0.85 0.71 0.52 0.59 0.65 0.65 0.75 0.86 0.64 0.96 0.83 0.83 0.84 0.86 0.89 0.92 0.86 0.88 0.9 0.93 0.89 0.85 0.88 0.89 0.65 0.76 0.74 0.87 0.78 0.82 0.87 0.88 0.76 0.89 0.92 0.87 0.76 0.76 0.8 0.88 0.98 0.94 0.89 0.86 0.94 0.68 0.81 0.83 0.97 0.81 0.83 0.84 0.5 0.94 0.59 0.82 0.83 0.68 0.8 0.86 0.59 0.94 0.67 0.68 0.51 0.98 0.55 0.93 0.92 0.72 0.68 0.63 0.55 0.66 0.9 0.66 0.8 0.83 0.86 0.57 0.62 0.71 0.59 0.99 0.66 0.61 0.58 0.63 0.57 0.56 0.8 0.59 0.59 0.52 0.72 0.87 0.67 0.75 0.65 0.69 PDP:2K6OAa PDP:2KKWAb d3cx5d2 PDP:2POHAc d1qcrd3 d3bkda1 d1kqfb2 PDP:2VOYK_ PDP:3AG3M_ PDP:3FWCBa PDP:3AG3I_ PDP:3G43Ea PDP:3FWBBa PDP:2K88A_ d1kilc_ PDP:3DEFAa d3cx5e2 d1jq1a_ d1n7sb_ PDP:2KHGA_ d2d00a1 d1t0hb_ PDP:2WI8Ab d1lw7a2 d1ihua2 d1vmaa2 PDP:2WOJAa d1t3la2 PDP:2Q8PAb PDP:3P2YAa d1ihua1 d1nrjb_ d1wa5a_ PDP:3QELBa PDP:3IPCAa d1ls1a2 PDP:2J37Wb PDP:2POHAa PDP:2KHKA_ PDP:3S8GC_ d2p7tc1 PDP:3BJ4Aa d1bdea_ PDP:3QELBb PDP:3HH8Ab d1nrza_ PDP:2OSVAb PDP:2OV6Aa PDP:2O1EAb d2r4qa1 d1lypa_ PDP:2ZXEGa PDP:2KYVA_ PDP:2KA1Aa d1t5ia_ PDP:3PEYAb d1nkta4 PDP:3BXZAc PDP:2FSHAd d1xtia2 d1iiba_ PDP:3IPRAa d1vkra_ PDP:3HH8Aa PDP:2FEWBa PDP:2O1EAa PDP:2OSVAa PDP:3P2YAb PDP:2VQ3Aa PDP:2AEFAa PDP:1Y4CAc PDP:3A3CAc PDP:3DM0Ac PDP:2GHAAc PDP:3N94Ab PDP:3Q27Ab d1l9la_ PDP:2B3FAb PDP:3A09Ab d1nkla_ d2gtga1 PDP:3BQPAa PDP:3SS1Ad d1of9a_ d1o82a_ PDP:2KJFAa PDP:3DDLAa d1djla_ d1d4oa_ PDP:2Q8PAa d2hmva1 d1shux_ PDP:2FN9Ab PDP:3L9WAa d1pdoa_ PDP:3RBZAb PDP:2WI8Aa d1id1a_ PDP:2FN9Aa PDP:3QJGAa PDP:2VOYIa PDP:3IPCAb d1kb9i_ d3cx5i1 PDP:2IYEAa PDP:3A1DAa PDP:2ZXEAa PDP:3CSGAb PDP:2VGQAb PDP:3C4MAb PDP:3IOWAc PDP:3F5FAc PDP:2XZ3Ac PDP:2FSHAa d1nkta3 PDP:3PEYAa d1t6na_ d1xtia1 PDP:2GEDAa PDP:3CIJAa PDP:2GHAAa PDP:3F5FAa PDP:3IOWAa PDP:3N94Aa PDP:2XZ3Aa PDP:2VGQAa PDP:2B3FAa PDP:3GZGAa PDP:1Y4CAa PDP:2O7IAa PDP:3A09Aa PDP:3Q27Aa PDP:3CSGAa PDP:3C4MAa PDP:2O1MAb PDP:3G3KAb PDP:2V25Ab PDP:3DM5Aa PDP:2QRYAb PDP:3U5ERc PDP:3CIJAb PDP:3GZGAb PDP:3G3KAa PDP:3A3CAa PDP:3DM0Aa PDP:2QRYAa PDP:2O1MAa PDP:2V25Aa PDP:2B4LAa d1u00a1 PDP:3D2FAb PDP:2LJ2A_ PDP:1WAZAa PDP:3FPPAc PDP:3AG3Bb PDP:3U5Eha d1bhaa_ PDP:3LOFAa PDP:3A5CGa PDP:3ICQTe PDP:2JAFAa PDP:1Y4CAd PDP:3BEHAa d1fftc_ d2j0na1 PDP:3AG3Ca d1xioa_ d1m0ka_ PDP:2QTSAa PDP:3EFFKa PDP:3PJSKa PDP:3A5CGb PDP:3FAVAa d1ujwb_ PDP:3FXDBa PDP:3FXDAa d1tkna_ PDP:3IAM1c d2vv5a3 PDP:3I8SAb PDP:3IAM4c PDP:3K1SAa d1zyma1 PDP:2WLLAb PDP:3RBZAa PDP:3BEHAb PDP:3OUFAa PDP:2I68Ab d1vrya1 PDP:3AG3J_ d1dkga2 PDP:2WW9B_ PDP:2J5DA_ PDP:2VOYGa d1nhla_ d1n7sd_ d1n7sa_ PDP:2VOYE_ PDP:2WX3A_ PDP:2OVCA_ d2hfed1 PDP:3HROAa PDP:2DOQDa PDP:3A2AAa PDP:2RDDBa PDP:3EFFKb PDP:2VOYH_ d1qled_ d1r48a_ PDP:2GV5Ca d1c17m_ d1orsc_ PDP:3EAMAb d2j0oa1 PDP:2QX5Ad PDP:3EGWCa d1qcrh_ PDP:3BXZAb PDP:2GUZBa PDP:3R8SYa PDP:3AG3Cb PDP:2NOOAa PDP:2KBIAa d2pq3a1 PDP:2XWUBb PDP:3TPOAa d1xqra1 PDP:2Z5KAc PDP:2XWUBc PDP:2ZHJAb PDP:3SS1Af PDP:4DDJAa PDP:3I5PAb d1bo9a_ PDP:1YGMAa PDP:2Z5KAb PDP:3ICQTf PDP:2Z5KAd PDP:3ICQTa PDP:2YVYAa PDP:3ICQTc PDP:2Z5KAa PDP:3ICQTd PDP:3FP3Ae PDP:2QX5Ac PDP:3G2SAa PDP:3AG3Ea PDP:2XWUBe PDP:1W99Aa PDP:3FP3Ad PDP:2IF4Ab PDP:3ICQTb PDP:3I5PAd d1hxia_ PDP:3FP3Ab PDP:2FSHAc d1ls1a1 PDP:3FP3Ac PDP:2EGDAa d1k8ua_ d1nkta2 PDP:3L9SAb d1vmaa1 PDP:3PGUAa d1v8qa_ PDP:3GF3Ac PDP:3MHSBa PDP:2V7YAa PDP:2IUSAb d1z5ye1 PDP:2GUZAa d3cx5f1 d1kb9f_ PDP:3CJHAa d2a06h1 PDP:3DXRAa PDP:3CJHB_ PDP:3DXRBa PDP:3I5PAa PDP:3IAM2b d1eeja1 PDP:3BS0Aa PDP:3CWWAe PDP:3ICQTg PDP:3I33Aa d2fwha1 PDP:3D2FAa PDP:3B9WAa PDP:3HD6Aa d1u7ga_ PDP:3NE5Bc PDP:2F1MAb PDP:3FPPAb PDP:2K33Aa PDP:2B2HAa PDP:3L9SAa PDP:1XEZAb d3c0na1 d1cwva5 d2fvya1 d1ewfa1 PDP:2VGQAc PDP:3S8GAa d1ffta_ PDP:2ZHJAa d1avca1 d1avca2 PDP:3F3FCb PDP:3AG3Aa PDP:3IGQAa d1cbya_ PDP:2IF4Aa PDP:2F4EAa PDP:3F7FAb PDP:2O5PAa PDP:2J8SAd PDP:3IAM4b PDP:2KEGA_ d2a5yb2 PDP:3EAMAa d1pp0a_ PDP:2J42Ac PDP:2AEFAb PDP:3RBZAc PDP:2HYID_ d1kqfa2 d1svpa_ PDP:3PV2Aa PDP:3GIAAa d2a65a1 d1g8ka1 d1g8ka2 PDP:3MI4Aa d1dg4a_ PDP:2ZS6Bc d8abpa_ d1efdn_ PDP:2J42Aa PDP:2V7YAb d2jdid3 d1vcla2 d1lkfa_ PDP:2DPYAb d1s62a1 d2rmwa1 d1ejqa_ PDP:3A5IAa d1rc9a2 PDP:2C1TC_ PDP:2VLQBa PDP:2H9XAa d1ntmi_ PDP:3JQOAb PDP:2K2BAa PDP:3H90Aa PDP:3RLFFb PDP:3MHSBb PDP:3TEWAc d1n0ua2 d1vlfm1 d1kqfa1 d1vlfm2 PDP:3JROAc PDP:3BG1Ba PDP:3NCXAb PDP:3D2FAe PDP:2V7YAc PDP:1XQSCb PDP:2K33Ab PDP:3CK6Aa d2bpta1 PDP:1WTHAc PDP:3NIRAa PDP:2IUSAc PDP:3U5EPa PDP:2YVYAc PDP:2ZY9Ab d1i4ja_ PDP:2J0ST_ PDP:3KSNAa PDP:3SS1Ae PDP:2R19Aa d1r6za1 PDP:3R8SUa d1ho8a_ d1ibaa_ PDP:2W84Aa PDP:3U5ECa PDP:3AG3Ha PDP:1ZPUAc PDP:3IAM3b PDP:1XEZAa d2mlta_ PDP:2W2DBa PDP:2ENKAa PDP:2ODXAa PDP:3CIOAa PDP:3RLFGa PDP:3AG3Fb d1pfoa_ PDP:3FIEC_ PDP:3FIIB_ PDP:3PIKAb d2hqsa2 d1sghb_ PDP:1WTHAg d1n0ua3 d2bbva_ PDP:3VI6Aa d1qcrd2 d1iq4a_ PDP:2R4FAa d1ciia2 PDP:3A5IAd d1ikpa1 PDP:2JPJA_ PDP:2J42Ab d1eeja2 d1tola1 PDP:2ZUQAa PDP:2WW9Aa PDP:3SZVAa PDP:3RW6Aa PDP:3CCDAa d1n0ua5 d2fgqx1 d1n0ua4 d1oo0b_ d2j0sd1 d2zfga1 PDP:2J8SAe d1rl6a1 d1rl6a2 d2qrra1 PDP:3TUICb PDP:2J8SAb d1fftb2 d3ehbb2 d2gsmb2 PDP:3SS1Ac PDP:2X9KAa d1uynx_ PDP:2QOMAa PDP:2WJRAa PDP:3NE5Ba d1tlya_ d1z05a3 PDP:3KVNAa PDP:3FP3Aa PDP:2Z5KAe PDP:3H90Ab PDP:1YJRAa d1aw0a_ PDP:3CJKBa PDP:3DXSXa d1oq3a_ PDP:3IWLAa d1cc8a_ PDP:2RMLAb PDP:2XWUBa PDP:2XWUBd PDP:3TPOAb PDP:3EBBAa PDP:3ICQTh PDP:2YVYAb PDP:2ZY9Aa PDP:3SS1Aa PDP:2HROAc PDP:2RMLAa PDP:2EW9Ab PDP:2ROPAb PDP:2EW9Aa d2vv5a2 PDP:3EX7Ba PDP:3FRYAa d1q8la_ d1mwya_ PDP:2VOYAa PDP:2AJ0Aa PDP:2J8SAc PDP:2J8SAf PDP:2GA7Aa PDP:2ROPAa PDP:4A1UAa PDP:2IMSAa d1fepa_ PDP:2HDIAa PDP:3PV2Ab d1r6ja_ PDP:3I33Ac PDP:3D2FAd d1w9ea1 PDP:3PV2Ac d1l6ta_ PDP:3OEEHb d2hfec1 PDP:2F1MAc PDP:2IH3Ca PDP:2I68Aa PDP:2Q67Aa PDP:3R8SMa PDP:3KFOAa d1r5sa_ PDP:3U5El_ PDP:3IAM9a PDP:2GWPA_ d1iwma_ PDP:2QDZAd d2a5yb1 PDP:3NE5Bb d1mc2a_ d3cx5d1 PDP:1YRTAb PDP:3AG3Da PDP:3BPPAa PDP:2DH2Ab PDP:3GQSAa PDP:2ZQKCa PDP:2ZW3Aa PDP:2FCGF_ PDP:3FEWXa d3deoa1 PDP:2A97Aa d3b60a2 PDP:3IAM4a PDP:2KKWAa d3bona1 d1t92a_ d1dfaa1 d3cx5e1 PDP:3D2FAc d1oaia_ PDP:2KHHAa d1go5a_ PDP:2NWFAa d1ewfa2 d1g8kb_ d1gppa_ PDP:3I33Ab d2grxc1 d1xx3a1 d1n2za_ d1toaa_ d1k0fa_ d1u07a_ d1hynp_ PDP:3CIOAb PDP:3BS6Aa PDP:2XU3Aa PDP:2QTSAb d1jdma_ PDP:2KZIAa PDP:3FEWXb d2d4ca1 PDP:3R8S4a PDP:3H4NAa d1u7la_ d1pfba_ PDP:2A06Ia d1dkga1 d1nkta1 PDP:3BK6Aa PDP:3L9WAb d1bcta_ PDP:2POHAb d1l2pa_ PDP:3HRNAa PDP:3U5ERb PDP:2BE6D_ d1kile_ PDP:1TY4C_ PDP:3HFEA_ PDP:2XZ3Ad PDP:2G9LA_ d1qcrk_ PDP:2LJTA_ d2fyuk1 PDP:3AG3K_ d1b9ua_ d1uuna_ PDP:2V9UAa d1ixha_ d1lsta_ PDP:2VPNAa d2a5sa1 d1wdna_ d1pb7a_ PDP:2R4FAc d2j0qd1 d3prna_ PDP:3INOAa PDP:3CWWAb d1oh2p_ d2a06b2 PDP:3CWWAc PDP:2FMAAa PDP:3KTMAb d2fkla1 PDP:2O4VAa d2mpra_ d1hr6b1 d2a06b1 d3cx5b1 d1hr6a1 d1hr6a2 d1hr6b2 d2a06a2 d3cx5b2 PDP:3CWWAa d3cx5a2 d3b60a1 PDP:2CBZAa PDP:2IXEAa d2pmka1 PDP:2NQ2Ca PDP:2PM7Ba d2a06a1 PDP:1YPHEa PDP:3TUICa d1b0ua_ PDP:2PZEAa d1oxxk2 PDP:2PM7Bb PDP:3AG3Ba d3ehbb1 PDP:1ZPUAa PDP:1ZPUAb PDP:1ZPUAd d1fftb1 PDP:3S8GBa d2gsmb1 PDP:2F1MAa d1cyxa_ PDP:3NCXAa d1svba1 PDP:3CSGAc d1b4ra_ d1cwva1 d1r9la_ d1nnfa_ d1xvxa_ d1r6za2 d2nvub2 d1elja_ d1pota_ d1ii5a_ d1q35a_ d1eu8a_ d1cwva4 PDP:3F3FAb PDP:3F3FAa PDP:2BBSAa d3cx5a1 PDP:2QI9Ca d1f86a_ d2v33a1 PDP:3HVDAb d1vlfn1 d1mjul2 PDP:3RY4Aa d1l6pa_ PDP:3TEWAb PDP:3I84Aa d3b5ha2 d1jpea_ d3b5ha1 PDP:3ESUFa PDP:3ESUFb PDP:2X1WLb PDP:2X1WLa d1cwva2 d1cwva3 d1mjuh1 PDP:2P45Ba PDP:2WLLAa PDP:2H0EAa PDP:2Q20Aa PDP:3N40Fc d1mjul1 PDP:3RY4Ab d1mjuh2 PDP:3NE5Bd PDP:3FPPAa d2jdid2 PDP:2DPYAa d2jdia2 PDP:3F7FAa PDP:3DM0Ad d2hqsa1 PDP:3JROAa d1xipa_ d1z05a1 d1prtb1 d2j5pa1 PDP:1Y4CAb d1prtd_ d1prtf_ d1c4qa_ PDP:3A3CAb PDP:2XZ3Ab PDP:3F5FAb PDP:3DM0Ab PDP:2GHAAb PDP:3IOWAb PDP:2QCPXa d1jkgb_ d1q40b_ d1jkga_ PDP:3R8STa d2fxta1 PDP:2CIUAa d1e8ob_ d1of5b_ PDP:3DWAAa PDP:3U5EXa d1ntva_ d1aqca_ d1e8oa_ PDP:3IKOCa d1h4ra2 PDP:3DXEAa PDP:2ZXEAc PDP:3DM5Ad PDP:2QJ6Ae d1kj6a_ d1h4ra3 d1hq1a_ PDP:2QJ6Ac PDP:2ROOAa d3d32a1 d1dula_ PDP:1ZMIA_ d1pw4a_ d3deoa2 PDP:3P6DAa d1gv9a_ d1dfaa2 PDP:1WTHAa PDP:3KVNAc PDP:3AG3Fa PDP:3HVDAc PDP:1YPHCa PDP:3TEWAd d1dska_ PDP:2IMUA_ d1bzka_ PDP:3I8SAc PDP:1LJZB_ PDP:3AG3L_ PDP:3KVNAd PDP:3R8S3a d1dfaa3 d1vcla3 d1ek9a_ PDP:3PIKAa PDP:4A17Wa PDP:2QDZAc PDP:2NQ2Aa PDP:3U5Eda PDP:3N40Fb d1e9ra_ PDP:3BXZAa PDP:2BPTB_ PDP:2GFPAa PDP:3PBPBa PDP:3RLFFc PDP:3KEPAa PDP:3RW6Ab PDP:3I8SAa d2ebfx3 PDP:2HDIBa PDP:1ZCDAa PDP:3RLFGb PDP:3R8SDb PDP:2QI9Aa PDP:3BP3Aa d1h4ra1 PDP:3DXEB_ PDP:3R8SCb PDP:3EAAAa d2cmza1 PDP:2J4USa PDP:1QCRI_ PDP:3F5FAd d1t1ua1 PDP:3A9JAa PDP:3JQOBa PDP:3R8SDc d2jdig1 PDP:3GF3Aa d1svba2 PDP:2D42Aa PDP:2AKHAa PDP:3BXZAd d1n69a_ PDP:3R8SEa PDP:2J37Wa d1agga_ PDP:2ZXEBa PDP:2NOOAc d1lf7a_ PDP:2ZF8Ab d1ry3a_ d2hqsc1 d1hi9a_ PDP:2QV3Ab d1fd3a_ PDP:2LCAAa PDP:2QV3Aa d1exra_ d1oo0a_ PDP:2W40Aa PDP:2JUIA_ PDP:3JQOC_ PDP:2NQ2Cc PDP:3EGWBd d1bh7a_ PDP:3I5QAa PDP:2QJYBb PDP:3IAM3e d1a3aa_ PDP:2D46Aa PDP:3CWWAd d1gd8a_ PDP:3R8SQa d1ibrb_ PDP:2QJYBc PDP:3O2UAa PDP:2W40Ab PDP:2QV3Ac PDP:3KVNAb PDP:3OEE1_ PDP:3EGWBe PDP:2KNEB_ PDP:2O7IAb PDP:3GF3Ab PDP:3R8S0_ PDP:3O79Aa PDP:2QJ6Aa PDP:3I5PAc PDP:2KOYAa PDP:3AG3Ga PDP:2ZXEAe PDP:1G5JB_ d1bdsa_ d1prta_ d3cx5c1 PDP:2NWLAa PDP:3IAM2a PDP:3DM5Ac PDP:2BL2Aa PDP:2VDAB_ PDP:2ZF8Aa PDP:2LAWA_ d1vp6a_ PDP:3MOLAa PDP:3FAVBa d1dfup_ PDP:2IUSAa PDP:3EGWBa d1uqwa_ d1xoca1 d1vr5a1 PDP:2KNIAa d1rh1a1 PDP:2FSHAb d1ikpa2 PDP:3ESSAa PDP:3I5PAe PDP:2HROAb PDP:3I5QAb PDP:3DM5Ab d1mhsa_ PDP:3A3CAd d1xtgb_ d1pxqa_ d1bgka_ d1dsja_ PDP:2QJ6Ab PDP:1WTHAf PDP:2ZXEAd PDP:2G7CAa PDP:2QJYBa PDP:1YTRA_ d3egvb1 PDP:3R8S2a d1em2a_ d1nrja_ PDP:1WXNAa PDP:3IAM3f PDP:3E7RLa PDP:2JTBA_ PDP:1WTHAb PDP:2O7IAc PDP:3RTLAa PDP:2A2VA_ d1jida_ d2a06f1 d1mfqb_ d1ahoa_ d2o6pa1 d3cx5g1 PDP:1WTHAd PDP:2B4LAb PDP:3U5EYa PDP:2VQIAa d1bywa_ PDP:3EGWBc d1t0ha_ d1t3la1 PDP:3ODVAa d1bk8a_ d2a06g1 d3cx5h1 PDP:3R8SEb PDP:2QP2Aa PDP:3U5ECb d1qcrg_ PDP:2DH2Aa PDP:2L5YAa PDP:3A5IAb PDP:2ZJSYb PDP:2ZJSYa PDP:2JP3A_ d1ikpa3 d1g6xa_ PDP:2WW9Ae PDP:3OEEHa d1fs0e2 d1qjpa_ d1fs0g_ d1k0ma1 d2vlqa1 PDP:3R8SLa PDP:3QRAAa PDP:3TUIAa d1kqfb1 d1vlfn2 d1kqfc_ d1plpa_ d3c0na2 PDP:3EGWBb PDP:2KLDAa d1mota_ PDP:2X1WAa d1wthd1 PDP:2A06J_ d3cx5c2 PDP:2WW9Ab PDP:2J8SAa PDP:3GKJAa PDP:3F7FAc d1z05a2 PDP:3IKOCb d1x32a1 PDP:2ZY9Ac d1bxya_ d1rc9a1 PDP:3R8SPa PDP:2OCTAb PDP:2WW9Ac d1wthd2 PDP:3IAM3d PDP:3JQOAa PDP:3EGWAa PDP:1YRTAc PDP:3HVDAa PDP:2R4FAb d1otsa_ PDP:3M4YAb PDP:3J01Ba PDP:3IAM3c PDP:3F3FCa d1v9ma_ PDP:2OCTAa PDP:2G3VAa PDP:2KSMAa PDP:3A5IAc d1ihra_ PDP:3R8SJb d1n0ua1 d1daba_ PDP:2JBXAa d2a5ya1 d1ohua_ PDP:3ILCAa PDP:2VOFAa d2k7wa1 d1k0ma2 d1q5la_ d1u00a2 PDP:3N8EAa PDP:3R8SOa PDP:1XQSCa PDP:2V7YAd PDP:2KRGAb PDP:3DH4Aa PDP:2RD7Aa PDP:2QQHAa d7ahla_ PDP:2G7CAc PDP:2F6EAa PDP:2G7CAb PDP:2QJ6Ad d1t5ra_ d1jeta_ d1prtb2 d2jdia3 PDP:2C61Aa PDP:3M4YAa d1jdpa_ d1tola2 d1vcla1 d1a8da2 d1guda_ PDP:3D2FAf PDP:3D9SAa PDP:3C02Aa PDP:3GD8Aa d1fx8a_ PDP:2O9GAa PDP:2F2BAa PDP:2QUOAa d2fe5a1 PDP:3CYYAa d1w9ea2 PDP:2KJDAa d1by5a_ PDP:3DDRAa PDP:1XKHAa d2gufa1 PDP:1XKWAa PDP:2O5PAb PDP:2QX5Ab PDP:3I33Ad PDP:2VU9Ab PDP:2FQXAa PDP:1XEZAc d1mfqc_ d1qb2a_ PDP:3TEWAa PDP:2ZS6Bb PDP:3A1DAb d2a29a1 PDP:2VOYJa PDP:2IYEAb PDP:2JLJAa PDP:2RPWX_ d1lw7a1 d1orqc_ PDP:3R8SCa d1mp1a_ d2huga1 PDP:2VOYB_ d1hz3a_ d2nvub1 PDP:3FEWXc PDP:3R8S1a PDP:3N40Fa PDP:3B5DAa d2df7a1 d1fs0e1 d1oxxk1 d2ebfx1 d2vv5a1 d1t1ua2 PDP:3HO6Aa PDP:3LMAAa d1diva1 d1gpra_ PDP:3R8SDa PDP:2QDZAb d2a7ub1 PDP:3RLFFa PDP:2QDZAa d1cw5a_ PDP:3U5ERa d2ebfx2 PDP:2JPKA_ d1ujla_ PDP:2QP2Ab PDP:2DPYAc PDP:3IAM6a PDP:3KTMAa d1mwpa_ PDP:3C4MAc d1zyma2 PDP:2HROAa PDP:3B7KAb PDP:3N94Ac PDP:3B7KAa PDP:2PZEAb PDP:2VU9Aa d1a8da1 PDP:3KQRAa PDP:3BG1Bb PDP:3FEWXd PDP:3M4YAc d1a87a_ PDP:2ETBAa PDP:3EU9Aa PDP:2J42Ad PDP:3T3LAa d1ew4a_ PDP:3IAM7a PDP:3TWRAa PDP:1YRTAa PDP:2KRGAa PDP:2VQGAa PDP:3IAM5a PDP:2WW9Af PDP:3IAM9b PDP:2NVJA_ PDP:2NOOAb PDP:2HC8Aa PDP:2WW9Ad PDP:3IAM1b PDP:2ZXEAb PDP:1WTHAe PDP:1XEZAd d1whia_ d1jo6a_ PDP:2POHAd d2a5yb3 d1diva2 d1qoya_ PDP:3SS1Ab PDP:3DP5Aa d1i8oa_ d2jdia1 d2jdid1 PDP:2C61Ab d2cfqa1 PDP:3CU4Aa PDP:2NLSAa PDP:3F3FCc PDP:2QX5Aa PDP:3JROAb PDP:2NQ2Cb PDP:3IAM3a PDP:3IAM1a d1ciia1 PDP:2I88Aa d1rh1a2 PDP:2CBZAb PDP:2IXEAb PDP:3TUICc

ISMB 2012 Poster - The Evolution of Protein Folds

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Protein function depends on the structure of a protein in the cell, and many significant changes in protein sequence are known which preserve 3D structure (eg circular permutations or fusion of interacting monomers). We discuss algorithms for detecting such rearrangements, and provide a framework for interpreting them in the context of evolution with the goal of explaining the emergence of novel protein folds. This poster was created for ISMB 2012. ABSTRACT The nature of protein fold space is hotly debated. Do the protein folds observed in nature fall into clean, discrete clusters, or is fold space more accurately modeled as a vast continuum, of which only a small sample of proteins has yet been observed? Previous efforts to answer this question have focused on geometric spaces (PCA, multidimensional scaling, locally linear embedding) or network models (conformational space networks) (Chodera, 2011). While such schemes may facilitate protein comparison and classification, the choice of a mathematical framework for fold space is arbitrary without a connection to concrete biological processes. To accurately capture the true relationships between protein folds, a model must consider the evolutionary history of those folds. Here we present a high-level model of protein evolution, which focuses on mutations that preserve the global 3D structure of proteins. We hypothesize that the combination of subtle local changes (e.g. PTMs) and large, but structure-preserving, rearrangements (e.g. duplications) can account for both the continuity of intermediate structures within protein folds and the evolution of seemingly novel folds. Our model categorizes known biological mutation processes, such as DNA replication errors and crossover errors, and places them in a simple theoretical framework. To test this model, we present evidence from the analysis of a recent systematic comparison of all protein domains from the Protein Data Bank (PDB). We also show that the model is consistent with existing evolutionary models for gene duplication, circular permuted proteins, and proteins with internal symmetry. Future work will focus on explicitly determining evolutionary events relating distantly homologous folds.

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Page 1: ISMB 2012 Poster  - The Evolution of Protein Folds

The Evolution of Protein FoldsSpencer Bliven

Department of BioinformaticsUniversity of California San Diego

Andreas PrlićSan Diego Supercomputer CenterUniversity of California San Diego

Philip BourneSkaggs School of Pharmacy and Pharmaceutical Sciences

University of California San Diego

Methods1.Identification of domain and subdomain architecture

a.Use SCOP domains where available, or calculate using the Protein Domain Parser (PDP) algorithm

b.Detect symmetry using CE-Symm (manuscript in preparation)

c.Detect circular permutations using CE-CP (Shindyalov, 2000; Prlic, 2010)

2.All-vs-all structural similarity calculationa.Filter representatives to 40% sequence identity

b.Use FATCAT algorithm (Ye and Godzik, 2003) to compare all protein domains from the Protein Data Bank (nearly 1 billion alignments, accessible from http://www.pdb.org)

3.Network analysisa.Filter out low-scoring structural alignments (TMScore≥0.5, Length≥25,

Coverage≥60%)

b.Map functional properties onto nodes: SCOP/CATH classification, GO terms, symmetry order, ligand information, etc.

4.Phylogenetic analysis (planned)Future work will center on quantifying the prevalence of subdomain rearrangement by integrating evolutionary data with the structural comparison data.

The nature of protein fold space is hotly debated. Do the protein folds observed in nature fall into clean, discrete clusters, or is fold space more accurately modeled as a vast continuum, of which only a small sample of proteins has yet been observed? Previous efforts to answer this question have focused on geometric spaces (PCA, multidimensional scaling, locally linear embedding) or network models (conformational space networks) (Chodera, 2011). While such schemes may facilitate protein comparison and classification, the choice of a mathematical framework for fold space is arbitrary without a connection to concrete biological processes. To accurately capture the true relationships between protein folds, a model must consider the evolutionary history of those folds.

Here we present a high-level model of protein evolution, which focuses on mutations that preserve the global 3D structure of proteins. We hypothesize that the combination of subtle local changes (e.g. PTMs) and large, but structure-preserving, rearrangements (e.g. duplications) can account for both the continuity of intermediate structures within protein folds and the evolution of seemingly novel folds. Our model categorizes known biological mutation processes, such as DNA replication errors and crossover errors, and places them in a simple theoretical framework.

To test this model, we present evidence from the analysis of a recent systematic comparison of all protein domains from the Protein Data Bank (PDB). We also show that the model is consistent with existing evolutionary models for gene duplication, circular permuted proteins, and proteins with internal symmetry. Future work will focus on explicitly determining evolutionary events relating distantly homologous folds.

Abstract

Poster first presented at the 20th Annual International Conference on Intelligent Systems for Molecular Biology (2012). Funded in association with the Protein Data Bank. The presentation of this work was made possible by a Travel Fellowship awarded by ISCB with grant funds obtained from the NIH NIMGS-National Institute of General Medical Sciences.

This work is licensed under the Creative Commons Attribution-NonCommercial 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA.

Model for the Evolution of New FoldsGiven these observations, we hypothesize that structure-preserving rearrangements are a major mechanism for the evolution of new protein folds. To test this, we classify mutations into the following categories:

1.Gene fusionA gene fusion occurs when two previously independent protein sequences are joined to create a single peptide product. This includes duplications, where the source sequence are identical, as well as the creation of chimeric proteins. To preserve function, the source proteins should either interact or form independently folding domains; other fusions are likely to be selected against.

2.Gene fissionA single peptide may split into two independently transcribed peptides. While a fission may be accompanied by the loss of the protein-protein interface, fissions which maintain the global structure of the protein are likely to be selected for.

3.Gain of protein-protein interfaceThe evolution of a new protein-protein interface results in a new quaternary structure. This may be either a heteromer, as shown in the diagram, or a homomer.

4.Loss of protein-protein interfaceProtein-protein interfaces may also be lost. This may occur in conjunction with fission.

5.Non-architectural mutationsAny mutation which does not alter the number of domains, binding, or connectivity is termed a non-architectural mutation. This includes insertions, deletions, and substitutions of amino acids or even whole secondary structures.

6.Order-disorder transitionsFor completeness, order-disorder transitions are included as a possible source of novel folds. However, such transitions are extremely difficult to detect, and are indistinguishable from primordial folds by the methods used in this study.

Principles of Protein Evolution1. Global structure is conserved in many significant rearrangements

2. Domains and subdomains are reused for many functions

(a) The TorD chaperon from Shewanella massilia (1N1C) is a dimer, but instead of each chain folding into a compact domain, each chain contributes to the structure or each domain. (b) The DmsD protein from Salmonella typhimurium (1S9U) has a very similar structure and has 20% sequence identity, but forms a monomer (Sippl, 2009).

(a) (b)

Domain Swapping Circular Permutation Symmetry(a)

(b) (c)

(a) Alignment of Regulatory Protein A from Human papillomavirus (1A7G) with AppA BLUF domain from Rhodobacter sphaeroides (2IYG). The two structures are related by a circular permutation, as can be seen from the rainbow coloring in (b) and (c)

The symmetric protein FGF-1 (3JUT), colored to highlight the 3-fold symmetry. Evidence suggests that ß-trefoils may have evolved from a trimeric precursor (Lee, 2011).

GTP binding regulator from Thermotoga maritima [1VR8] consists of two αβββ motifs, colored orange and yellow. The half-glyoxalase query motif (cyan) is aligned for comparison.

Structure of glyoxalase I from E. coli [3HDP]. Colors show the two-fold symmetry of the protein around its nickel-binding site.

Dimer form of glyoxalase I [1F9Z], colored by chain. Relative to 3HDP, the symmetric motifs are swapped between chains.

1,2‑dihydroxynaphthalene dioxygenase [2EHZ] from Pseudomonas (orange/grey) consists of four copies of the half-glyoxalase motif (cyan). Iron is bound at the active site.

FusionFission

Loss of interface

Gain of interface

ConclusionWe aim to provide a model for analyzing protein fold space based not on geometric properties, but on evolutionary relationships. This approach avoids the dichotomy of "continuous" and "discrete". Our model is derived from the observation that many proteins which are currently classified as belonging to separate folds can be decomposed into subdomains which appear in many different subdomain architectures.

The evolution of protein symmetry is a prime example of this phenomenon. Proteins may be symmetric at the level of quaternary structure, tertiary structure, or both. Significant homology can often be detected between the repeated subunits of symmetric proteins, suggesting that symmetry evolves by duplication and fusion events. These events preserve the protein-protein interaction interfaces and the global structure of the protein, providing a plausible pathway for radical fold change without non-functional intermediates. Likewise, the currently accepted models for the evolution of circular permutations can be couched as a special case of the model presented here (Weiner, 2006).

To investigate the evolution of protein folds as broadly as possible, an extensive all-vs-all comparison of domains from the Protein Databank was conducted. This consisted of nearly one billion pairwise alignments, and was performed on the Open Science Grid distributed cluster. This wealth of data allows the clustering of potentially homologous domains. Research is ongoing to incorporate evolutionary information into this network, with the ultimate goal of quantifying the prevalence of each mechanism for fold evolution.

Chodera & Pande (2011) PNAS. vol.108(32) pp. 12969–12970

Lee & Blaber (2011) PNAS, vol.108 (1) pp. 126–130Prlic et al. (2010) Bioinformatics. vol. 26 (23) pp.

2983-2985

Shindyalov and Bourne (2000) Proteins. vol. 38 (3) pp. 247-60

Sippl (2009) Curr Opin Struct Biol. vol.19 (3) pp. 312-20

Thornalley (1993) Mol. Aspects Med. 14 (4) pp. 287–371Ye and Godzik (2003). Bioinformatics. vol. 19(Suppl 2),

pp. ii246–55.Weiner & Bornberg-Bauer (2006) Mol. Biol. Evol. vol.

23(4) pp. 734–743

Case Study: Transmembrane Proteins

(Left) Structural similarities between domains of transmembrane proteins, as classified by the Transporter Classification Database (TCDB). A moderate threshold of TM‑Score≥0.5 was used, leaving the network fairly sparse. The nodes are colored according to their TCDB classification.

(Right) Enlargement of the boxed section of the graph, with 3D structures overlaid. All structures are similar to the Rossmann fold, but several are classified in different SCOP folds (e.g. PTS system IIB component-like (d1iiba_)). A wide diversity of TCDB functions are annotated to the structurally similar cluster.

PDP:2AEFAa PDP:3IPRAa

PDP:2FN9Ab

d1iiba_

d2r4qa1

PDP:3L9WAa

d1pdoa_

PDP:3A1DAa

d1djla_d1shux_

d1d4oa_

d1nrjb_

PDP:2IYEAa

PDP:2FN9Aa

PDP:2ZXEAa

PDP:2VOYIa

d1wa5a_

PDP:3QELBa

PDP:3QELBb

PDP:2O1EAb

d1nrza_

PDP:2OSVAa

PDP:2OSVAb

PDP:3HH8Aa

PDP:2O1EAa

PDP:3HH8Ab

PDP:3IPCAb

PDP:2Q8PAa

d1id1a_

d2hmva1

PDP:2WI8Aa

PDP:3QJGAa

PDP:3P2YAb

d1ls1a2

PDP:2FEWBa

PDP:3RBZAb

d1vkra_PDP:2VQ3Aa

PDP:3IPCAa

1.0

0.90.8

0.7

Transmembrane Electron Carriers

Channels/Pores

Incompletely Characterized

Transport Systems

Group Translocators

Accessory Factors Involved

in Transport

Primary Active

Transporters

Electrochemical Potential-driven

Transporters

Legend:Color indicates TCDB ClassEdge weight indicates TM-Score

0.5

0.64

0.52

0.57

0.54

0.53 0.530.58 0.65

0.66

0.75

0.65

0.52

0.53

0.63

0.57

0.55

0.75

0.58

0.60.56

0.64

0.73

0.730.61

0.66

0.71

0.59

0.58

0.77

0.5

0.64

0.52

0.5

0.51

0.54

0.6

0.530.67

0.60.7

0.67

0.53

0.51

0.66

0.560.61

0.6

0.650.52

0.54

0.58

0.7

0.520.69

0.77

0.57

0.56

0.53

0.5

0.76

0.54

0.610.65

0.560.59

0.55

0.570.61

0.55

0.69

0.5

0.550.670.65

0.54

0.58

0.64

0.5

0.53

0.68

0.56

0.51

0.5

0.52

0.61

0.530.55

0.62

0.620.58

0.61

0.5

0.67

0.8

0.58

0.84

0.69

0.690.68

0.52

0.6

0.56

0.550.6

0.60.55

0.550.55

0.560.52

0.58

0.55

0.510.67

0.55

0.680.62

0.58

0.7

0.67

0.56

0.64

0.650.55

0.640.61

0.57 0.50.67

0.62

0.72

0.51

0.64

0.53

0.69

0.58

0.62

0.56

0.56

0.5

0.5

0.6

0.51

0.53

0.84 0.510.780.7

0.60.78

0.54

0.52

0.5

0.530.5

0.540.52

0.62

0.62

0.560.55

0.55

0.69

0.61

0.6

0.72

0.81

0.58 0.87

0.58

0.78

0.61

0.52

0.85

0.57

0.53

0.530.74

0.55

0.790.81

0.84

0.670.68

0.61

0.67

0.73

0.59

0.77

0.57

0.59

0.81

0.88

0.5

0.57

0.57

0.6

0.65

0.71

0.59

0.50.57

0.54

0.620.53

0.660.65

0.57

0.74

0.51

0.58

0.590.69

0.7 0.76

0.72

0.8

0.87

0.53

0.830.73

0.7

0.62

0.76

0.660.67

0.70.58

0.6

0.6

0.690.78

0.66

0.53

0.54

0.670.53

0.620.71 0.53

0.79

0.56

0.52

0.58

0.66

0.750.71

0.740.69

0.62

0.68

0.63

0.55

0.55

0.65

0.55

0.68

0.740.66

0.68

0.6

0.52

0.69

0.6

0.72

0.830.59

0.910.6

0.74

0.52

0.59

0.71

0.76

0.73

0.54

0.52

0.94

0.52

0.54

0.73

0.53

0.53

0.51

0.5

0.54

0.64

0.62

0.82

0.59

0.71

0.9

0.66

0.51

0.84

0.73

0.51

0.52

0.72

0.59

0.56

0.53

0.61

0.7

0.67

0.52

0.63

0.82

0.53

0.610.550.5

0.93

0.530.55

0.5

0.59

0.52

0.620.52

0.50.56

0.53

0.68

0.56

0.56

0.610.57

0.5

0.55

0.540.65

0.61

0.560.5

0.69

0.54

0.620.56

0.53

0.62

0.57

0.69

0.65

0.77

0.58 0.66

0.67

0.650.77

0.79

0.77

0.76

0.61

0.53

0.58

0.73

0.65

0.76

0.78

0.530.6

0.52

0.56

0.84

0.54

0.77

0.78

0.75

0.56

0.78

0.76

0.62

0.820.79

0.850.83

0.82

0.77

0.98

0.65

0.55

0.610.55

0.74

0.72

0.59

0.56 0.820.52

0.69

0.5

0.64

0.78 0.870.7

0.58

0.82

0.58

0.66

0.55

0.87

0.56

0.72

0.51

0.58

0.62

0.65

0.61

0.56

0.57

0.51

0.64

0.52

0.64

0.67

0.55

0.69

0.57

0.56

0.52

0.62

0.58

0.56

0.53

0.51

0.55

0.72

0.52

0.66

0.73

0.530.54

0.52

0.5

0.5

0.5

0.52

0.5

0.65

0.51

0.53

0.59

0.53

0.56

0.57

0.510.5

0.57

0.53

0.5 0.55

0.5

0.52

0.530.55

0.6

0.56

0.52

0.56

0.52

0.5

0.58

0.53

0.56

0.56

0.58

0.5

0.71

0.54

0.58

0.52

0.65

0.56

0.75

0.6

0.59

0.66

0.61

0.52

0.63

0.51

0.59

0.540.5

0.51

0.65

0.54

0.68

0.71

0.89

0.65

0.85 0.68

0.67

0.52

0.550.52

0.5

0.52

0.7

0.6

0.85

0.6

0.590.6

0.64

0.5

0.56

0.65

0.88

0.78

0.56

0.63

0.560.56

0.95

0.51

0.66

0.51

0.620.66

0.64

0.65

0.55

0.52

0.56

0.65

0.52

0.52

0.52

0.57

0.52 0.6

0.58

0.92

0.5

0.54

0.63

1.0

0.5

0.53

0.57

0.53

0.51

0.53 0.67

0.90.84

0.53

0.570.51

0.630.53

0.53

0.51

0.51

0.83

0.640.60.63

0.55

0.68

0.56

0.53

0.620.69

0.65

0.54

0.66

0.62

0.880.54

0.97 0.84

0.89

0.57

0.55

0.51

0.99

0.99

0.89

0.990.99

0.97

0.53

0.97

0.54

0.970.97

0.88

0.980.991.0

0.53

0.89

1.00.89

0.53

0.880.89

0.880.88

0.870.881.0

0.990.980.98

0.58

0.991.0

0.74

0.99

0.7

1.00.980.99

0.57

0.991.0

0.73

0.99

0.72

0.71 0.76

0.5

0.79 0.73

0.64

0.74

0.62

0.74

0.710.720.7

0.69

0.5

0.52

0.8

0.51

0.55

0.7

0.5

0.51

0.5

0.5

0.57

0.58

0.86

0.80.77

0.51

0.550.56

0.99

0.57

0.51

0.530.55

0.5

0.5

0.52

0.5

0.52

0.780.5

0.520.53

0.53

0.82

0.8

0.570.88

0.6

0.540.65

0.57

0.56 0.57

0.67

0.59

0.870.6

0.81

0.6

0.51

0.870.58

0.6

0.63

0.510.56

0.51

0.54

0.55

0.55

0.59

0.58

0.510.55

0.61

0.97

0.64

0.87

0.52

0.96

0.53

0.52

0.82

0.80.72

0.990.99

0.980.98

0.59

1.0

1.0 1.01.00.99

0.58

1.00.99

0.58

1.0

0.59

0.52

0.5

0.6

0.990.99

0.570.55

0.590.6

1.0

0.59

0.56 0.52

0.5

0.6

0.74

0.9

0.69

0.70.72

0.720.76

0.89

0.910.95

0.78

0.780.78

0.790.77

0.57

0.88

0.780.78

0.83

0.79

0.58

0.8

0.790.780.57

0.85

0.51

0.930.92

0.920.92

0.93

0.82

0.61

0.81 0.87

0.910.92

0.870.92

0.58

0.92

0.79

0.99

0.95

0.98

0.79

0.990.991.0

0.77

1.0

0.61

0.57

0.991.0

0.940.780.940.92

0.940.950.94

0.79

0.94

0.62

0.59

0.940.95

0.990.78

0.78

0.980.99

0.991.0

0.78

1.0

0.61

0.58

0.990.99

0.930.79

0.79

0.6

0.940.990.98

1.0

0.8

0.991.0

0.78

0.571.0

0.780.94

1.0 0.99

0.62

0.990.98

0.78

0.99

0.77

0.57

0.79

0.8

0.79

0.57

0.770.82

0.770.78

0.740.79

0.790.790.79

0.59

0.790.78

0.53

0.86

0.57

0.99

0.57 0.98

0.62

0.78 0.94

0.990.99

0.73

0.620.59

0.60.570.61

0.67

0.970.97 0.96

0.910.8

0.940.93

0.56

0.930.77

0.980.99

0.57

0.79

0.64

0.63

0.720.54

0.66

0.73

0.61

0.63

0.51

0.76

0.55

0.67

0.58

0.50.54

0.76

0.5

0.820.78

0.99

0.57

0.78

0.580.55

0.780.54

0.59

0.760.55

0.73 0.68

0.83

0.53

0.6

0.51

0.55

0.55

0.5

0.51

0.5

0.51

0.5

0.66

0.69

0.57

0.5

0.62

0.660.59

0.73

0.84

0.67

0.83

0.53

0.6

0.620.71

0.6

0.610.5

0.72

0.61 0.830.55

0.56

0.53

0.520.56

0.530.5

0.59

0.580.51

0.5

0.5

0.63

0.57

0.59

0.560.64

0.62

0.51

0.57

0.51

0.72

0.570.64

0.5

0.51

0.57

0.51

0.58

0.61

0.510.5

0.93

0.910.5

0.6

0.82

0.6

0.51

0.57

0.64

0.52

0.76

0.58

0.50.52

0.87

0.5

0.93

0.60.5

0.51

0.57

0.88

0.620.53

0.5

0.54

0.55

0.55

0.51

0.53

0.57

0.920.76

0.51

0.73

0.560.6

0.54

0.53

0.75

0.76

0.85

0.68

0.73

0.57

0.7

0.58

0.58

0.59

0.74

0.74

0.83

0.64

0.56

0.61

0.53

0.51

0.67

0.51

0.580.66

0.7 0.55

0.52

0.51

0.57

0.67

0.54 0.72

0.54

0.72

0.61

0.64

0.89

0.57

0.52

0.5

0.5

0.53

0.54

0.69

0.74

0.63

0.570.56

0.51

0.530.55

0.51

0.51

0.57

0.5

0.5

0.61

0.56

0.5

0.53

0.64

0.57

0.51

0.52

0.52

0.5

0.61

0.52

0.86

0.8

0.76

0.71

0.75

0.69

0.57

0.5

0.76

0.91

0.8

0.74

0.86

0.57 0.6

0.56

0.72

0.58

0.66

0.62

0.55

0.63

0.57

0.58

0.53

0.540.56

0.54

0.6

0.53

0.640.57

0.53

0.610.51

0.51

0.53

0.50.6

0.66

0.640.55

0.51

0.64

0.590.74

0.5

0.52

0.53

0.69

0.59

0.730.68

0.790.63

0.58

0.770.55

0.780.53

0.57

0.64

0.80.67

0.74

0.55

0.51

0.660.51

0.53

0.62

0.670.57

0.5

0.55

0.5

0.85

0.83

0.71

0.780.54

0.67

0.59 0.67

0.730.73

0.58

0.8

0.62

0.74

0.62

0.84

0.81

0.76

0.77

0.54

0.81

0.63

0.56

0.840.83

0.8

0.66

0.53

0.54 0.7

0.62

0.69

0.77

0.61

0.63

0.59

0.61

0.57

0.68

0.92

0.59

0.55

0.57

0.71

0.65

0.74

0.64

0.5

0.59

0.75

0.66

0.73

0.590.67 0.79

0.74

0.680.64

0.5

0.56 0.67

0.69

0.65

0.59

0.61

0.56

0.59

0.5

0.6

0.57

0.57

0.5

0.54

0.66

0.55

0.65

0.5

0.6

0.55

0.740.56

0.71

0.55

0.58

0.56

0.62

0.5

0.55

0.67

0.57

0.63

0.56

0.60.7

0.53

0.52

0.59

0.72

0.52

0.64

0.67

0.61

0.59

0.71

0.64

0.580.67

0.72

0.55

0.51

0.56

0.51

0.51

0.56

0.58

0.56

0.5

0.650.56

0.54

0.58

0.55

0.61

0.81

0.7

0.57

0.610.64

0.57

0.57

0.52

0.51

0.52

0.7

0.54

0.75

0.5

0.57

0.57

0.61

0.6

0.54

0.7

0.59

0.560.64

0.72

0.62

0.7

0.76

0.710.62

0.68

0.74

0.680.63

0.62

0.6

0.78

0.5 0.54

0.53

0.51

0.53

0.52

0.51

0.51

0.71

0.57

0.71

0.63

0.53

0.61

0.51

0.58

0.62

0.64

0.51

0.63

0.68

0.60.57

0.5

0.51

0.5

0.53

0.74

0.69

0.66

0.55

0.6

0.6

0.57 0.58

0.53

0.630.72

0.53

0.540.54

0.53

0.51

0.540.52

0.54

0.65

0.62

0.57

0.61

0.77

0.59

0.52

0.52

0.52

0.54

0.5

0.58

0.57

0.64

0.51

0.52

0.54

0.59

0.55

0.53

0.53

0.52

0.64

0.55

0.6

0.55 0.54

0.54

0.69

0.52

0.78

0.5

0.63

0.56

0.83 0.66

0.85

0.61

0.5

0.62

0.76

0.53

0.5

0.52

0.51

0.51

0.5

0.51 0.53

0.84

0.98

0.5

0.64

0.55

0.99

0.88

0.88

0.71

0.75

0.75

0.87

0.82

0.81

0.51

0.55

0.64

0.5

0.55

0.51

0.93

0.52

0.54

0.52

0.54

0.84

0.92

0.870.8

0.82

0.91

0.74 0.75

0.71

0.84

0.8 0.75

0.52

0.6

0.72 0.73

0.7

0.52

0.6

0.56

0.67

0.81

0.59

0.75

0.69

0.56

0.81

0.850.83

0.96

0.960.96

0.96

0.570.56

0.93 0.83

0.97

0.82

0.920.89

0.61

0.770.63

0.640.72

0.73

0.640.57

0.71

0.720.59

0.670.69 0.56

0.7

0.69

0.55

0.69

0.57

0.7

0.69

0.77

0.570.61

0.9

0.53

0.95 0.630.840.91

0.78

0.89

0.870.81

0.730.73

0.92

0.76

0.91

0.750.73

0.90.76

0.52

0.53

0.7

0.68

0.7

0.54

0.94

0.57

0.93

0.840.930.89

0.89

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