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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…. NSDSECPLSHDG || || | || NSYPGCPSSYDG. NSDSECPLSHDG. ?.

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homology modeling

Homology Modeling

Seminar produced by Hanka Venselaar

homology modeling1
Homology modeling

Yes we can

% identity

*

# residues

* Actually, modelling is possible here, but we cannot get an alignment…

homology modeling in short

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

1 template recognition and initial alignment
1: Template recognition and initial alignment
  • BLAST your sequence against PDB
  • Best hit  normally template
slide7

2: Alignment correction

1: Template recognition and initial alignment

2 alignment correction

CPISRTAAS-FRCW

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

2 alignment correction1

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

slide10

3: Backbone generation

2: Alignment correction

1: Template recognition and initial alignment

3 backbone generation
3: Backbone generation
  • Making the model….
  • Copy backbone of template to model
  • Make deletions as discussed
  • (Keep conserved residues)
slide12

4: Loop modeling

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4 loop modeling
4: Loop modeling

Known structure GVCMYIEA---LDKYACNC

Your sequence GECFMVKDLSNPSRYLCKC

Loop library,

try different options

slide14

5: Sidechain modeling

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5 side chain modeling
5: Side-chain modeling
  • Several options
  • Libraries of preferred rotamers based upon backbone conformation
slide16

6: Model optimization

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5: Sidechain modeling

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

*

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

slide18

2: Alignment correction

1: Template recognition and initial alignment

3: Backbone generation

4: Loop modeling

5: Sidechain modeling

7: Model validation

6: Model optimization

7 model validation
7: Model Validation
  • Second opinion by PDBreport /WHAT IF
  • Errors in active site?  new alignment/ template
  • No errors?  Model!
slide20

2: Alignment correction

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

slide21

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

8 steps of homology modeling

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

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