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Homology modeling in short…

Homology modeling in short…. Prediction of structure based upon a highly similar structure. 2 basic assumptions: Structure defines how sequence defines function During evolution structures are more conserved than sequence. Use one structure to predict another. Homology modeling. Yes we can.

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Homology modeling in short…

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  1. Homology modeling in short… • Prediction of structure based upon a highly similar structure • 2 basic assumptions: • Structure defines how sequence defines function • During evolution structures are more conserved than sequence Use one structure to predict another

  2. Homology modeling Yes we can % identity O * # residues * Actually, modelling is possible here, but we cannot get an alignment… O Example: by 80 residues  30% identity is (just) sufficient

  3. NSDSECPLSHDG || || | || NSYPGCPSSYDG NSDSECPLSHDG ? Alignment of model and template sequence Unknown structure Known structure Back bone copied Homology modeling in short… Prediction of structure based upon a highly similar structure Model! Copy backbone and conserved residues Add sidechains, Molecular Dynamics simulation on model Known structure

  4. The 8 steps of Homology modeling

  5. NSDSECPLSHDGYCLHDGVC || || | ||||| ||| NSYPGCPSSYDGYCLNGGVC 1: Template recognition and initial alignment • BLAST your sequence against PDB • Best hit  normally template • Initial alignment 

  6. E I E E V V A P C C C S R R M R G L M P P 2: Alignment correction -A-V F-D- • Core residues  conserved • Use multiple sequence alignments • Deletions in your sequence  shift gaps Known structure FDICRLPGSAEAV Model FNVCRMP---EAI Model FNVCR---MPEAI  Correct alignment

  7. 3: Backbone generation • Making the model…. • Copy backbone of template to model • Make deletions as discussed • (Keep conserved residues)

  8. 5: Side-chain modeling • Several options • Libraries of preferred rotamers based upon backbone conformation

  9. 6: Model optimization • Molecular dynamics simulation • Remove big errors • Structure moves to lowest energy conformation

  10. 7: Model Validation • Second opinion by PDBreport /WHAT IF • Errors in active site?  new alignment/ template • No errors?  Model!

  11. 2: Alignment correction 1: Template recognition and initial alignment 3: Backbone generation 4: Loop modeling 8: Iteration 8: Iteration 5: Sidechain modeling Model! 8: Iteration 8: Iteration 7: Model validation 6: Model optimization

  12. Alignment Modeling Correction 8 steps of homology modeling 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Side-chain modeling 6: Model optimization 7: Model validation 8: Iteration

  13. Force Fields…. Force fields are used most prominently for: Template detection and sequence alignment Side chain modelling (and loop modelling) Model optimization (by MD) Structure and model validation (next seminar)

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