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Applications of Homology Modeling Hanka Venselaar.

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Presentation on theme: "Applications of Homology Modeling Hanka Venselaar."— Presentation transcript:

1 Applications of Homology Modeling Hanka Venselaar

2 This seminar…. Homology Modeling… Why? What? When? How? And a few real world examples….

3 Homology modeling Example: by 80 residues  30% identity sufficient # residues % identity * * Actually, modelling is possible, but we cannot get an alignment… O

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

5 The 8 steps of Homology modeling

6 1: Template recognition and initial alignment

7 BLAST your sequence against PDB Best hit  normally template Initial alignment  NSDSECPLSHDGYCLHDGVC || || | ||||| ||| NSYPGCPSSYDGYCLNGGVC

8 1: Template recognition and initial alignment 2: Alignment correction

9 Functional residues  conserved Use multiple sequence alignments Deletions  shift gaps CPISRTGASIFRCW CPISRTA---FRCW CPISRT---AFRCW CPISRTAAS-FRCW CPISRTG-SMFRCW CPISRTA--TFRCW CPISRTAASHFRCW CPISRTGASIFRCW CPISRTA---FRCW Both are possible Multipe sequence alignment Correct alignment  Sequence with known structure  Your sequence

10 2: Alignment correction Core residues  conserved Use multiple sequence alignments Deletions in your sequence  shift gaps Known structure FDICRLPGSAEAV Model FNVCRMP---EAI Model FNVCR---MPEAI S G P L A E R C IV C R M P E V C R M P E  Correct alignment F-D- -A-V

11 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation

12 Making the model…. Copy backbone of template to model Make deletions as discussed (Keep conserved residues)

13 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling

14 Known structure GVCMYIEA---LDKYACNC Your sequence GECFMVKDLSNPSRYLCKC Loop library, try different options

15 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling

16 5: Side-chain modeling Several options Libraries of preferred rotamers based upon backbone conformation

17 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization

18 Molecular dynamics simulation Remove big errors Structure moves to lowest energy conformation

19 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization 7: Model validation

20 7: Model Validation Second opinion by PDBreport /WHATIF Errors in active site?  new alignment/ template No errors?  Model!

21 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization 7: Model validation 8: Iteration

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

23 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 Alignment Modeling Correction

24 Homology Modeling… What? Prediction of an unknown structure based on an homologous and known structure Why? To answer biological and medical questions when the “real” structure is unknown When? A template with enough identity must be available How? 8 Steps To conclude….

25 And now…. After the next seminar go to the course website: Thanks to Hanka Venselaar for making nearly all slides in this seminar.


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