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Protein Homology Modeling
Introduction• What is protein?
- providing energy- building/repairing tissue in body
• Amino Acids- protein is made up of amino acids.- 20 standard amino acids
Introduction• Sequence
- string represent the primary structure of the protein
Primary structure
3D structure
Introduction• Homology Modeling refers to constructing an
model of the "target" protein from its amino acid sequence and/or an experimental 3D structure (the "template")
?
Introduction• Homology Modeling
o When we want to know the 3D structure of a protein(target) that has not been solved
o You have only the sequence
o If there exist a solved experimental 3D structure(template) is similar to target protein
o We can use software to arrange the backbone of the sequence.
Model Production
Step 1 - Template Selection
Step 2 - Target-Template Alignment
Step 3 - Model Construction
Step 4 - Model Validation
Step 1. Template Selection
• First step in homology modeling is the identification of the best template structure.
• The simplest method of template identification relies on database search techniques such as BLAST.
Step 1. Template Selection
• BLAST(Basic Local Alignment Search Tool)Input: sequenceOutput: templates with Identities, E-value …
Step 2. Target-Template Alignment• Comparison between target & template.
• Used to generate the model of protein.
Step 3. Model Construction
• Fragment assemblyrelied on the assembly of a complete model from
closely related solved structures.
• Segment matchingdivides the target into short segments, matched
to its own template fitted from the Protein Data Bank.
• Spatial restraint basedcommon software used is MODELLER.
Step 4. Model Validation
• An example:Tool: Errat
Model SelectionThe Protein Model Portal
• ModWeb• M4T• Swiss Model• I-TASSER• HHpred
PMP Work Flow
z
z
Swiss Model
Model SelectionServer Pdb files Model Name
Hhpred 1 (Chun)HHpred
I-TASSER 3 (Chun)I-TASSER model1 C-score=1.13(Chun)I-TASSER model2 C-score=-1.39(Chun)I-TASSER model3 C-score=0.70
M4T 1 (Chun)M4T
ModelWeb 2 (Chun)ModelWeb Model_fd(Chun)ModelWeb Model_f5
Swiss Model 1 (Chun)SwissModel
Model Selection
SequenceDifferentServer
pdb1
pdb2
pdb3
pdb4
pdb5
……
best pdb ?
Model SelectionModel Name Errat(overall
quality factor)
Verify 3D( percentage of the residues had an averaged 3D-1D score
> 0.2)
Prove(Z score)
(Chun)HHpred 86.856 93.52% 0.349
(Chun)I-TASSER model1 45.153 93.52% -0.075
(Chun)I-TASSER model2 48.329 77.31% 0.042
(Chun)I-TASSER model3 52.806 87.78% -0.176
(Chun)M4T 77.041 92.52% -0.137
(Chun)ModelWeb Model_fd
77.836 96.12% 0.050
(Chun)ModelWeb Model_f5
76.350 91.46% 1.196
(Chun)SwissModel 85.492 93.42% 0.302
Conclusion
• Homology modelingo Input sequence -> Template -> Build Model -> Validation
• Need understand and use tools well
• It cost time to validate model
Questions?