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Prediction of Protein 3D Structure I-Comparative Modelling

Prediction of Protein 3D Structure I-Comparative Modelling. Inter-University DEA/DES Bioinformatics 2000-2001 Shoshana J. Wodak, SCMBB-ULB. Prediction of protein 3D structure. sequence. KELVLVLYDY QEKSPRELTI KKGDILTLLN STNKDWWKVE VNDRQGFIPA AYLKKLD. Similar sequence with

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Prediction of Protein 3D Structure I-Comparative Modelling

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  1. Prediction of Protein 3D Structure I-Comparative Modelling Inter-University DEA/DES Bioinformatics 2000-2001 Shoshana J. Wodak, SCMBB-ULB

  2. Prediction of protein 3D structure sequence KELVLVLYDY QEKSPRELTI KKGDILTLLN STNKDWWKVE VNDRQGFIPA AYLKKLD Similar sequence with Known 3D structure is identified Similar sequence(s) found, but no info on 3D structure No similar sequence is identified Homology modelling Fold recognition no yes ? ? 3D structure

  3. Homology modelling Main steps 1.Identify the protein with known structure, the template, related to the target protein 2. Align the target sequence to the known structure 3. Build the model (1.) and (2.) are very crucial step

  4. Homology modelling Building the model MODELLING THE WHOLE FOLD 1. Rigid-body assembly 2. Spare-parts approach 3. Satisfaction of spatial restraints MODELLING LOOPS 1. Database search of segments fitting fixed end-points 2. Molecular mechanics, molecular dynamics 3. Combination of 1+2 MODELLING SIDE CHAIN CONFORMATIONS 1.Use of rotamer libraries (backbone dependent) 2. Molecular mechanics optimization 3. Mean-field methods

  5. Modeling loops KELV---------LVLYDY QEKSPRELSQTI KKGDILTLLN STNKDWWKVE KDLVGNDRLVLYDY QDKSIREL-----TI KTGDILTLLN STQKDWWKVH Insertions/deletions: loops of target and template are of different lengths, Different length loops, with different structures Backbone structure of loops needs to be modelled

  6. Modeling loops 1. Database search for segments from known protein structures fitting fixed end-points 2. Molecular mechanics, molecular dynamics 3. Combination of 1+2

  7. Model conformations of side chains -Model side chains of residues that differ in seq. between the target and template -Re-model side chains of residues with same seq. as in target

  8. Modelling side chain conformations 1.Use of side chain conformations in known protein structures 2. Molecular mechanics optimization 3. Mean-field methods -Rotamer libraries -Dead-End Elimination (heuristic) -Monte-Carlo (heuristic) -Branch & Bound (exact)

  9. Modelling side chain conformations A combinatorial problem residue position protein backbone -8 0 -14 0 -5 +5 all rotamers of at this position rotamer selected for this position

  10. Modelling side chain conformations Backbone usually limits rotamer conformational freedom

  11. Side-chain modeling (BPTI) Red : X-ray Blue : models obtained by Monte Carlo sampling

  12. Modelling of surface side chains, SH3 domain D14 E16 M48 D30 R46 K31 D41 L7 E2 N DESIGNER (Wernisch et al., 2000) Using Dead End Elimination + Branch & Bound (c) C

  13. Modelling core side chains, SH3 domain Y3F D17Q N N C C V39I L5V (a) SH3 (b) protein G C I30V N (c) ubiquitin DESIGNER Wernisch et al., 2000 V26L

  14. Modelling side chain conformations with DESIGNER (Wernisch et al., 2000) Using Dead End Elimination + Branch & Bound

  15. Modelling side chain conformations DESIGNER versus other common methods Only one rotamer predicted at the same time All rotamers predicted together DESIGNER Wernisch et al. 2000

  16. Homology modelling How accurate need your model be? Accurate for what? Define the precise goal of your modelling study - Design ligand that bind specifically - Rationalise functional differences relative to related proteins - Rationalise effect of mutations - Identify surface that binds a cognate molecules? - Analyse surface properties Active site defined to < 1Å rmsd Mutation/binding region ~1Å rmsd model globally correct Model accuracy/reliability is highly dependent on the sequence identity level between target & template see discussion: http://www.expasy.ch/swissmod/SM_LikelyPrecision.html

  17. Homology modelling Widely used homology modelling servers/programs -Swiss-Model (E. Peitsch, Glaxo,Geneva) http://www.expasy.ch/swissmod/SWISS-MODEL.html -Modeller (A. Sali/Rockefeller U. USA) http://guitar.rockefeller.edu/modeller/modeller.html Other homology modelling servers/programs -3D-Jigsaw (M. Sternberg, ICRF, UK) http://www.bmm.icnet.uk/people/paulb/3dj/form.html

  18. Homology modelling Remaining problems/bottlenecks? -identifying an adequate template -orthologs/analogs -obtaining the correct alignment -simple sequence alignments, not enough, need for multiple alignments, HMM? -modelling loops

  19. Schematic Model (trypsin)

  20. Surface model (trypsin)

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