homology modeling
DESCRIPTION
Homology Modeling. Seminar produced by Hanka Venselaar. Homology modeling. Yes we can. % identity. *. # residues. * Actually, modelling is possible here, but we cannot get an alignment…. NSDSECPLSHDG || || | || NSYPGCPSSYDG. NSDSECPLSHDG. ?. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/1.jpg)
Homology ModelingHomology Modeling
Seminar produced by Hanka Venselaar
![Page 2: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/2.jpg)
Homology modeling
# residues
% id
entit
y
*
* Actually, modelling is possible here, but we cannot get an alignment…
Yes we can
![Page 3: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/3.jpg)
Homology modeling in short…Prediction of structure based upon a highly similar structure
Add sidechains, Molecular Dynamics simulation on model
Unknown structure
NSDSECPLSHDG
NSDSECPLSHDG
|| || | ||
NSYPGCPSSYDG
Alignment of model and template sequence
Known structure
Known structure Back bone copiedCopy backbone and conserved residues
Model!
![Page 4: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/4.jpg)
The 8 steps of Homology modeling
![Page 5: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/5.jpg)
1: Template recognition and initial alignment
![Page 6: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/6.jpg)
1: Template recognition and initial alignment
• BLAST your sequence against PDB
• Best hit normally template
![Page 7: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/7.jpg)
1: Template recognition and initial alignment
2: Alignment correction
![Page 8: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/8.jpg)
2: Alignment correction
• Functional residues conserved• Use multiple sequence alignments• Deletions shift gaps
CPISRTGASIFRCW CPISRTGASIFRCWCPISRTA---FRCW CPISRT---AFRCW
CPISRTAAS-FRCWCPISRTG-SMFRCWCPISRTA--TFRCWCPISRTAASHFRCWCPISRTGASIFRCW CPISRTA---FRCW
Both are possible
Multipe sequence alignment
Correct alignment
Sequence with known structure
Your sequence
![Page 9: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/9.jpg)
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
I V
C
R
M
P
EV
C
R M
P
E
Correct alignment
F-D--A-V
![Page 10: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/10.jpg)
1: Template recognition and initial alignment
2: Alignment correction
3: Backbone generation
![Page 11: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/11.jpg)
3: Backbone generation
• Making the model….• Copy backbone of template to model• Make deletions as discussed• (Keep conserved residues)
![Page 12: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/12.jpg)
1: Template recognition and initial alignment
2: Alignment correction
3: Backbone generation
4: Loop modeling
![Page 13: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/13.jpg)
4: Loop modeling
Known structure GVCMYIEA---LDKYACNC
Your sequence GECFMVKDLSNPSRYLCKC
Loop library,
try different options
![Page 14: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/14.jpg)
1: Template recognition and initial alignment
2: Alignment correction
3: Backbone generation
4: Loop modeling
5: Sidechain modeling
![Page 15: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/15.jpg)
5: Side-chain modeling
• Several options• Libraries of preferred rotamers based
upon backbone conformation
![Page 16: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/16.jpg)
1: Template recognition and initial alignment
2: Alignment correction
3: Backbone generation
4: Loop modeling
5: Sidechain modeling
6: Model optimization
![Page 17: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/17.jpg)
6: Model optimization
• Molecular dynamics simulation• Remove big errors
• Structure moves to lowest energy conformation*
* Which has nothing to do with the real coordinates...
![Page 18: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/18.jpg)
1: Template recognition and initial alignment
2: Alignment correction
3: Backbone generation
4: Loop modeling
5: Sidechain modeling
6: Model optimization
7: Model validation
![Page 19: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/19.jpg)
7: Model Validation
• Second opinion by PDBreport /WHAT IF• Errors in active site? new alignment/
template
• No errors? Model!
![Page 20: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/20.jpg)
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: Iteration8: Iteration
8: Iteration
8: Iteration
![Page 21: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/21.jpg)
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: Iteration8: Iteration
8: Iteration
8: Iteration
![Page 22: Homology Modeling](https://reader036.vdocuments.site/reader036/viewer/2022062520/56815e79550346895dccfc77/html5/thumbnails/22.jpg)
8 steps of homology modeling1: Template recognition and initial alignment2: Alignment correction3: Backbone generation4: Loop modeling5: Side-chain modeling6: Model optimization7: Model validation8: Iteration
Alignment
Modeling
Correction