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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


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


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)


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


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


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...


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!


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


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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