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## PowerPoint Slideshow about ' Homology Modeling' - archie

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### 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…

|| || | ||

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

1: Template recognition and initial alignment

- BLAST your sequence against PDB
- Best hit normally template

1: Template recognition and initial alignment

CPISRTG-SMFRCW

CPISRTA--TFRCW

CPISRTAASHFRCW

CPISRTGASIFRCW

CPISRTA---FRCW

CPISRTGASIFRCW CPISRTGASIFRCW

CPISRTA---FRCW CPISRT---AFRCW

Correct alignment

2: Alignment correction- Functional residues conserved
- Use multiple sequence alignments
- Deletions shift gaps

Multipe sequence alignment

Sequence with known structure

Your sequence

Both are possible

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

3: Backbone generation

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

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

Known structure GVCMYIEA---LDKYACNC

Your sequence GECFMVKDLSNPSRYLCKC

Loop library,

try different options

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5: Side-chain modeling

- Several options
- Libraries of preferred rotamers based upon backbone conformation

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5: Sidechain modeling

6: Model optimization

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

*

Which has nothing to do with the real coordinates...

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5: Sidechain modeling

7: Model validation

6: Model optimization

7: Model Validation

- Second opinion by PDBreport /WHAT IF
- Errors in active site? new alignment/ template
- No errors? Model!

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

8: Iteration

8: Iteration

5: Sidechain modeling

8: Iteration

8: Iteration

7: Model validation

6: Model optimization

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

Modeling

Correction

8 steps of homology modeling1: 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

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