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Jürgen Sühnel jsuehnel@imb-jena.de

3D Structures of Biological Macromolecules Exercise 1: Structural Comparison of Proteins. Jürgen Sühnel jsuehnel@imb-jena.de. Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany.

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Jürgen Sühnel jsuehnel@imb-jena.de

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  1. 3D Structures of Biological Macromolecules Exercise 1: Structural Comparison of Proteins Jürgen Sühnel jsuehnel@imb-jena.de Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany Supplementary Material: http://www.fli-leibniz.de/www_bioc/3D/

  2. N Quantitative Structural Comparison of Protein Structures Root Mean Square Deviation • The RMSD is a measure to quantify structural similarity • Requires 2 superimposed structures (designated here as “a” & “b”) • N = number of atoms being compared RMSD = S (xai - xbi)2+(yai - ybi)2+(zai - zbi)2

  3. Comparing Protein Structures • Two steps: • Identification of a set of related atom pairs • Superposition with minimum RMSD value

  4. Comparing Protein Structures

  5. Comparing Protein Structures

  6. Comparing Protein Structures http://www.ruppweb.org/xray/comp/suptext.htm

  7. Quaternions

  8. Quaternions

  9. Comparing Protein Structures

  10. Comparing Protein Structures

  11. Comparing Protein Structures http://wishart.biology.ualberta.ca/SuperPose/

  12. Comparing Protein Structures http://www.ebi.ac.uk/DaliLite/

  13. Comparing Protein Structures http://cl.sdsc.edu/

  14. Comparing Protein Structures – SuperPose Server Beginning with an input PDB file or set of files, SuperPosefirst extracts the sequences of all chains in the file(s). Eachsequence pair is then aligned using a Needleman–Wunschpairwise alignment algorithm. If the pairwise sequence identity falls below the defaultthreshold (25%), SuperPose determines the secondary structureusing VADAR (volume, area, dihedral angle reporter) andperforms a secondary structure alignment using a modified Needleman–Wunschalgorithm. After the sequence or secondary structure alignmentis complete, SuperPose then generates a difference distance(DD) matrix between aligned alpha carbon atoms. A differencedistance matrix can be generated by first calculating the distancesbetween all pairs of C atoms in one molecule to generate aninitial distance matrix. A second pairwise distance matrix isgenerated for the second molecule and, for equivalent/alignedCalpha atoms, the two matrices are subtracted from one another, yieldingthe DD matrix. From the DD matrix it is possible to quantitativelyassess the structural similarity/dissimilarity between two structures.In fact, the difference distance method is particularly good at detecting domain or hinge motions in proteins. SuperPose analyzes the DD matrices and identifies thelargest contiguous domain between the two molecules that exhibits<2.0 Å difference. From the information derived fromthe sequence alignment and DD comparison, the program then makesa decision regarding which regions should be superimposed andwhich atoms should be counted in calculating the RMSD. Thisinformation is then fed into the quaternion superposition algorithmand the RMSD calculation subroutine. The quaternion superpositionprogram is written in C and is based on both Kearsley's method and the PDBSUP Fortran program developed by Rupp and Parkin. Quaternions were developed by W. Hamilton (the mathematician/physicist)in 1843 as a convenient way to parameterize rotations in a simple algebraic fashion. Because algebraic expressions are more rapidlycalculable than trigonometric expressions using computers, thequaternion approach is exceedingly fast. SuperPose can calculate both pairwise and multiple structuresuperpositions [using standard hierarchical methods andcan generate a variety of RMSD values for alpha carbons, backboneatoms, heavy atoms and all atoms (average and pairwise). Whenidentical sequences are compared, SuperPose also generates ‘perresidue’ RMSD tables and plots to allow users to identify,assess and view individual residue displacements. http://wishart.biology.ualberta.ca/SuperPose/

  15. SuperPose Server: Examples Identical/same sequence but different structure Calmodulin: 1A29 vs. 1CLL (open and closed form) Similar structure but slightly different sequence length Thioredoxin: 3TRX vs. 2TRX_a Similar structure but extremely different sequence Thioredoxin/Glutaredoxin: 3TRX vs. 3GRX_1 http://wishart.biology.ualberta.ca/SuperPose/

  16. Calmodulin

  17. Thioredoxin

  18. Glutaredoxin InterPro

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