Protein Structure Prediction
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Transcript Protein Structure Prediction
Biomolecular Modeling (practical)
Dr. Kong Lesheng
Temasek Life Sciences Laboratory (TLL)
([email protected])
Objective
To predict 3D structure with good quality
when given a protein sequence
Protein structure prediction
Comparative (homology) modeling
– typically >20-30% identity
Threading/fold recognition
– cannot detect similarity in sequence level
Ab initio (de novo) modeling
– cannot detect fold
Adapted from
Sali & Baker,
Science (2001)
Adapted from
Sali & Baker,
Science (2001)
Comparative modeling
More reliable and accurate
Computationally less intensive
With the development of structural
genomics project, most modeling
problem will be reduced to comparative
modeling!
Before modeling
Check Protein Data Bank (PDB)
– e.g. NCBI BLAST against PDB
Check Model Databases
– SWISS-MODEL Repository
• http://swissmodel.expasy.org/repository/
– Modbase
• http://modbase.compbio.ucsf.edu/
– Caution! Those models generated by
automated comparative modeling
Few Terms
Target
– Protein sequence without structure
Template
– Known protein structure sharing detectable
sequence similarity with target sequence
Model
– Predicted 3D structure
Comparative Modeling procedure
Template selection
Target-template alignment
Model building
Model evaluation
Comparative modeling
Automated server
– SDPMOD
– SWISS-MODEL
– 3D-JIGSAW
Standalone program
– Modeller
– WHATIF
Modeling using automated server
If target is small disulfide-rich
proteins (SDPs), try SDPMOD
– Length < 100 a.a. & Cys > 4
– http://proline.bic.nus.edu.sg/sdpmod/
Else, try SWISS-MODEL
– http://swissmodel.expasy.org/
A sample output by SDPMOD
http://proline.bic.nus.edu.sg/sdpmod/cgi-bin/view.py?ukey=IPC03gMxvN
Model Evaluation
Stereochemistry quality checking
– Procheck
– Whatcheck
Wrong fold vs. correct fold
– ProSA II
– Verify_3D
SAVS:Structure Analysis and
Validation Server
http://nihserver.mbi.ucla.edu/SAVS/
Want to know more?
Sali Lab
– http://salilab.org/modeller/modeller.html
Baker lab
– http://robetta.bakerlab.org/
CASP (Critical Assessment of techniques
for protein Structure Prediction)
– http://predictioncenter.gc.ucdavis.edu/casp7/
Any question?
Modeling by Modeller
Template selection
Target-template alignment
Model building
Model evaluation
An example
Target: influenza hemagglutinin
(Swissprot ID: Q67087)
>Target
METISLITILLVVTVSNADKICIGYQSTNSTETVDTLTENNVPVTHAKELLHTEHNGMLCATNLGHPLIL
DTCTIEGLIYGNPSCNLLLGGREWSYIVERPSAVNGLCYPGNVENLEELRSLFSSASSFQRIQIFPDTIW
NVSYSGTSKACSDSFYRSMRWLTQKNNTYPIQDAQYTNNRGKSILFMWGINHPPTDTVQTNLYTRTDTTT
SVATEDINRTFRPLIGPRPLVNGQQGRIDYYWSVLKPGQTLRVRSNGNLIAPWYGHILSGESHGRILKTD
LNSGNCVVQCQTERGGLNTTLPFHNVSKYAFGNCPKYVGVKSLKLAVGLRNVPARSSRGLFGAIAGFIEG
GWSGLVAGWYGFQHSNDQGVGMAADRDSTQRAIDKITSKVNNIVDKMNKQYEIIDHEFSEVETRLNMINN
KIDDQIQDIWAYNAELLVLLENQKTLDEHDANVNNLYNKVKRALGSNAVEDGKGCFELYHKCDDQCMETI
RNGTYNKRKYKEESRLERQKIEGVKLESEGTYKILTIYSTVASSLVIAMGFAAFLFWAMSNGSCRCNICI
NCBI BLAST against PDB
Template selection
Download template structure
Target-template alignment
Needle at EMBOSS server
– http://sf01.bic.nus.edu.sg/EMBOSS/
Jalview
– http://www.jalview.org/
>Target
DKICIGYQSTNSTETVDTLTENNVPVTHAKELLHTEHNGMLCATNLGHPLIL
DTCTIEGLIYGNPSCNLLLGGREWSYIVERPSAVNGLCYPGNVENLEELRSLFSSASSFQRIQIFPDTIW
NVSYSGTSKACSDSFYRSMRWLTQKNNTYPIQDAQYTNNRGKSILFMWGINHPPTDTVQTNLYTRTDTTT
SVATEDINRTFRPLIGPRPLVNGQQGRIDYYWSVLKPGQTLRVRSNGNLIAPWYGHILSGESHGRILKTD
LNSGNCVVQCQTERGGLNTTLPFHNVSKYAFGNCPKYVGVKSLKLAVGLRNVPARSSRGLFGAIAGFIEG
GWSGLVAGWYGFQHSNDQGVGMAADRDSTQRAIDKITSKVNNIVDKMNKQYEIIDHEFSEVETRLNMINN
KIDDQIQDIWAYNAELLVLLENQKTLDEHDANVNNLYNKVKRALGSNAVEDGKGCFELYHKCDDQCMETI
RNGTYNKRKYKEESRLERQKIEGVKLESEGTYKILTIYSTVASSLVIAMGFAAFLFWAMSNGSCRCNICI
>1JSD
DKICIGYQSTNSTETVDTLTETNVPVTHAKELLHTSHNGMLCATNLGHPLILDTCTIEGLIYGNPSCDLL
LGGREWSYIVERPSAVNGMCYPGNVENLEELRSLFSSASSYQRIQIFPDTIWNVSYSGTSSACSDSFYRS
MRWLTQKNNAYPIQDAQYTNNRGKSILFMWGINHPPTDTVQTNLYTRTDTTTSVTTEDINRTFKPVIGPR
PLVNGLHGRIDYYWSVLKPGQTLRVRSNGNLIAPWYGHILSGESHGRILKTDLNSGNCVVQCQTERGGLN
TTLPFHNVSKYAFGNCPKYVGVKSLKLAVGLRNVPARSSGLFGAIAGFIEGGWPGLVAGWYGFQHSNDQG
VGMAADSDSTQKAIDKITSKVNNIVDKMNKQYGIIDHEFSEIETRLNMINNKIDDQIQDIWTYNAELLVL
LENQKTLDEHDANVNNLYNKVKRALGSNAMEDGKGCFELYHKCDDQCMETIRNGTYNRRKYKEESKLERQ
KIEGI
Format the alignment in PIR format