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

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

4. The 8 steps of Homology modeling

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

6. 2: Alignment correctionS G P L A E R C I V C R M P E V C R M P E
-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. 1: Template recognition and initial alignment
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. 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

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)