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Homology modelling

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by

Hanka Venselaar

on 2 April 2014

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Transcript of Homology modelling

8: Iteration

8: Iteration

7: Model
validation

Model!

1: Template recognition and initial alignment

2: Alignment correction

6: Model optimization

5: Sidechain modeling

4: Loop
modeling

3: Backbone
generation

Homology
Modelling

8: Iteration
Best hit is usually your template

BLAST your sequence against PDB











1: Template recognition
and initial alignment

BLAST your sequence against PDB











1: Template recognition
and initial alignment

Best hit is usually your template

Initial alignment

BLAST your sequence against PDB











1: Template recognition
and initial alignment

Concept 1: Functional residues must be conserved

2: Alignment correction
- Sequence with known structure
- Your sequence

Multipe sequence alignment

CPISRT
A
AS -FRCW
CPISRT
G
- SMFRCW
CPISRT
A
- -TFRCW
CPISRT
A
A SHFRCW
CPISRT
G
A S IFRCW
CPISRT
A
- - -FRCW

CPISRT
G A
SI FRCW CPISRTG A S
I
FRCW
CPISRT
A
- - - FRCW CPISRT - - -
A
FRCW

Concept 2: Use multiple sequence alignments

2: Alignment correction

E

R

C

M

V

L

V

E

P

R

C

P

V
C

R

E

A

M
P

G

S

Known structure FDVCRLP GSA EAV

Model FNVCRMP- - - EA I

Model FNVCR- - - MPEA I

Concept 3: Deletions in your sequence? -> shift gaps

2: Alignment correction
Making the model….
- Copy backbone of template to model
- Make deletions as discussed
- Keep conserved residues


3: Backbone generation

Several options
Libraries of preferred rotamers based on backbone conformation

5: Side-chain modeling

6: Model optimization

Molecular dynamics simulation
Remove big errors


Structure moves to lowest energy conformation

7: Model Validation

Second opinion by PDBreport /WHATIF
Errors in active site? -> new alignment/ template


No errors? -> Model!

Loop library,
try different options

Known structure GVCMYLEA - - - LDKYACNC
Your sequence GECFMVKDLSNPSRYLCKC

4: Loop modeling

-Find another template / correct the backbone / perform better loop modelling
Start over
Use one structure to predict another

Basic assumptions:

1) Structure defines function
2) During evolution structures are more conserved than sequence

Prediction of structure based upon a highly similar structure

Homology modeling in short…

Homology modeling – When?
Full transcript