swiss-model: giving the proteome a third dimension. torsten schwede fortaleza, brasil 1. august 2006...
TRANSCRIPT
SWISS-MODEL:
Giving the proteome a third dimension.
Torsten Schwede
Fortaleza, Brasil 1. August 2006
Schweizerisches Institut für BioinformatikInstitut Suisse de BioinformatiqueIstituto Svizzero di BioinformaticaSwiss Institute of Bioinformatics
Introduction
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tatcaagcaggacataacaaggtaggatctctacagtacttggcactaacagcattagtaagaccaagaaaaaagataaagccacctttgcctagtgttacaaaactgacagaggatagatggaacaagccccagaagaccaagggccacaaagggaaccatacaatgaatggacactagaacttttagaggagctcaagaatgaagctgttagacattttcctaggatatggctccatagcttagggcaacatatctatgaaacttatggagatacttgggcaggagtggaagccataataagaattctgcaacaactgctgtttattcatttcagaattgggtgtcaacatagcagaatagacattcttcgacgaaggagagcaagaaatggagccagtagatcctagactagagccctggaagcatccaggaagtcagcctaggactgcttgtaccaattgctattgtaaaaagtgttgctttcattgccaagtttgtttcataacaaaaggcttaggcatctcctatggcaggaagaagcggagacagcgacgaagagctcctcaagacagtcagactcatcaagtttctctatcaaagcagtaagtagtacatgtaatgcaatctttacaaatattagcagtagtagcattagtagtagcagcaataatagcaatagttgtgtggtccatagtattcatagaatataggaaaataagaagacaaaacaaaatagaaaggttgattgatagaataatagaaagagcagaagacagtggcaatgagagtgacggagatcaggaagaattatcagcacttgtggaaatggggcacgatgctccttgggatgttaatgatctgtaaagctgcagaaaatttgtgggtcacagtttattatggggtacctgtgtggaaagaagcaaccaccactctattttgtgcctcagatgctaaagcgtatgatacagaggtacataatgtttgggccacacatgcctgtgtacccacagaccccaacccacaagaagtagaactgaagaatgtgacagaaaattttaacatgtggaaaaataacatggtagaccaaatgcatgaggatataattagtttatgggatcaaagcctaaagccatgtgtaaaattaaccccactctgtgttactttaaattgcactgattatgggaatgatactaacaccaataatagtagtgctactaaccccactagtagtagcgggggaatggaggggagaggagaaataaaaaattgctctttcaatatcaccagaagcataagagataaagtgaagaaagaatatgcacttttttatagtcttgatgtaataccaataaaagatgataatactagctataggttgagaagttgtaacacctcagtcattacacaggcctgtccaaaggtatcctttgaaccaattcccatacattattgtgccccggctggttttgcgattctaaagtgtaatgataaaaagttcaatggaaaaggaccatgtacaaatgtcagcacagtacaatgtacacatggaattaggccagtagtatcaactcaactgctgttaaatggcagtctagcagaagaagaggtagtaattagatcagacaatttctcggacaatgctaaagtcataatagtacatctgaatgaatctgtagaaattaattgtacaagactcaacaacattacaaggagaagtatacatgtaggacatgtaggaccaggcagagcaatttatacaacaggaataataggaaaaataagacaagcacattgtaacattagtagagcaaaatggaataacactttaaaacagatagttacaaaattaagagaacaatttaagaataaaacaatagtctttaatcaatcctcaggaggggacccagaaattgtaatgcacagttttaattgtggaggggaatttttctactgtaattcaacacaactgtttaacagtacttggaatggtactgcatggtcaaataacactgaaggaaatgaaaatgacacaatcacactcccatgcagaataaaacaaattataaacatgtggcaggaagtaggaaaagcaatgtatgcacctcccatcagaggacaaattagatgttcatcaaatattacagggctgatattaacaagagatggtggtattaaccagaccaacaccaccgagattttcaggcctggaggaggagatatgaaggacaattggagaagtgaattatataaatataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcaaagagaaaaaagagcagtgggaataataggagctatgctccttgggttcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagacaattattgtctggtatagtgcaacagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcacctcacagtctggggcatcaagcagctccaagcaagagtcctggctgtggaaagatacctaagggatcaacagctcctggggttttggggttgctctggaaaactcatttgcaccactgctgtgccttggaatactagttggagtaataaatctctgagtcagatttgggataacatgacctggatgcagtgggaaagggaaattgataattacacaagcttaatatacaacttaattgaagaatcgcaaaaccaacaagaaaagaatgaacaagagttattggaattagataactgggcaagtttgtggaattggtttagcataacaaattggctgtggtatataaaaatattcataatgatagtaggaggcttggtaggtttaagaatagtttttactgtactttctatagtaaatagagttaggcagggatactcaccattgtcgtttcagacgcgcctcccagccaggaggggacccgacaggcccgaaggaatcgaagaagaaggtggagagagagacagagacagatccggtcaattagtggatggattcttagcaattatctgggtcgacctgcggagcctgtgcctcttcagctaccaccgcttgagagacttactcttgattgtaacgaggattgtggaacttctgggacgcagggggtgggaagccctcaaatattggtggaatctcctacaatattggattcaggaactaaagaatagtgctgttagcttgctcaacgccacagccatagcagtagctgagggaactgatagggttatagaagtattacaaagagcttgtagagctattctccacatacctagaagaataagacagggcttagaaagggctttgcaataagatgggtggtaagtggtcaaaaagtagtaaaattggatggcctactgtaagggaaagaatgagaagagctgagccagcagcagatggggtgggagcagtatctcgagacctggaaaaacatggagcaatcacaagtagtaatacagcaactaacaatgctgattgtgcctggctagaagcacaagaggaggaggaggtgggttttccagtcagacctcaggtacctttaagaccaatgacttacaagggagcgttagatcttagccactttttaaaagaaaaggggggactggaagggctaatttggtcccagaaaagacaagacatccttgatttgtgggtccaccacacacaaggctacttccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggttggtgcttcaagctagtaccagttgagccagagaaggtagaagaggccaatgaaggagagaacaacagattgttacaccctgtgagcctgcatgggatggaggacccggagaaagaagtgttagtatggaggtttgacagccgcctagtactccgtcacatggcccgagagctgcatccggagtactacaaggactgctgacactgagctttctacaagggactttccgctggggactttccagggaggcgtggcctgggcgggactggggagtggcgagccctcagatgctgcatataagcagctgctttttgcctgtactgggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttca
gggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctgatagctagagatcccttcagaccaaatttagtcagtgtgaaaaatctctagcagtggcgcctgaacagggacttgaaagcgaaagagaaaccagagaagctctctcgacgcaggactcggcttgctgaagcgcgcacggcaagaggcgaggggacggcgactggtgagtacgccaaaattttgactagcggaggctagaaggagagagatgggtgcgagagcgtcgatattaagcgggggaggattagatagatgggaaaaaattcggttaaggccagggggaaagaaaaaatatagattaaaacatttagtatgggcaagcagggagctagaacgattcgcagtcaatcctggcctattagaaacatcagaaggttgtagacaaatactgggacaactacaaccagcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctctattgtgtgcatcaaaagatagatgtaaaagacaccaaggaagctttagataagatagaggaagagcaaaacaaaagtaagaaaaaagcacagcaagcagcagctgacacaggaaatagcagccaggtcagccaaaattaccccatagtgcagaacatccaggggcaaatggtacatcaggccatatcacctagaactttaaatgcatgggtaaaagtagtagaagagaaggctttcagcccagaagtaatacccatgttttcagcattatcagaaggagccaccccacaagatttaaacaccatgctaaacacagtggggggacatcaagcagccatgcaaatgttaaaagagaccatcaatgaggaagctgcagaatgggatagattgcatccagtgcatgcagggcctcatccaccaggccagatgagagaaccaaggggaagtgacatagcaggaactactagtacccttcaggaacaaatagcatggatgacaaataatccacctatcccagtaggagaaatctataagagatggataatcctgggattaaataaaatagtaaggatgtatagccctaccagcattctggacataaaacaaggaccaaaggaaccctttagagactatgtagaccggttctataagactctaagagccgagcaagcttcacaggaggtaaaaaattggatgacagaaaccttgttggtccaaaatgcgaacccagattgtaagactattttaaaagcattgggaccagcagctacactagaagaaatgatgacagcatgtcagggagtgggaggacccggccataaagcaagagttttggcagaagcaatgagccaagtaacaaattcagctaccataatgatgcagaaaggcaattttaggaaccaaagaaaaattgttaagtgtttcaattgtggcaaagaagggcacatagccaaaaattgcagggcccctaggaaaaggggctgttggaaatgtggaaaggagggacaccaaatgaaagattgtactgagagacaggctaattttttagggaaaatctggccttcccacaggggaaggccagggaattttcctcagaacagactagagccaacagccccaccagccccaccagaagagagcttcaggtttggggaagagacaacaactccctctcagaagcaggagctgatagacaaggaactgtatccttcagcttccctcaaatcactctttggcaacgaccccttgtcacaataaagataggggggcaactaaaggaagctctattagatacaggagcagatgatacagtattagaagaaataaatttgccaggaagatggaaaccaaaaatgatagggggaattggaggttttatcaaagtaagacagtatgatcaaatactcgtagaaatctgtggacataaagctataggtacagtattagtaggacctacacctgtcaacataattggaagaaatctgttgactcagattggttgcactttaaattttcccattagtcctattgaaactgtaccagtaaaattaaagccaggaatggatggcccaaaagttaaacaatggccattgacagaagaaaaaataaaagcattagtagaaatctgtacagaaatggaaaaggaaggaaaaatttcaaaaatcgggcctgaaaatccatataatactccagtatttgccataaagaaaaaagacagtactaaatggagaaaattagtagatttcagagaacttaataagaaaactcaagacttctgggaagttcaattaggaataccacatcccgcagggttaaaaaagaaaaaatcagtaacagtactggatgtgggtgatgcatatttttcagttcccttagataaagaattcaggaagtacactgcatttaccatacctagtataaacaatgagacaccagggattagatatcagtacaatgtgcttccacagggatggaaaggatcaccagcaatattccaaagcagcatgacaaaaatcttagagccttttagaaaacaaaatccagacatagttatctatcaatacatggacgatttgtatgtaggatctgacttagaaatagggcagcatagaacaaaaatagaggaactgagacaacatctgttgaagtggggatttaccacaccagacaaaaaacatcagaaagaacctccattcctttggatgggttatgaactccatcctgataaatggacagtacagcctatagtgctgccagaaaaggacagctggactgtcaatgacatacagaagttagtgggaaaattgaattgggcaagtcagatttacccagggattaaagtaaagcaattatgtagactccttaggggaaccaaggcactaacagaagtaataccactaacaaaagaagcagagctagaactggcagaaaacagggaaattctaaaagaaccagtacatggagtgtattatgacccatcaaaagacttaatagcggaaatacagaagcaggggcaaggtcaatggacatatcaaatttatcaagagccatttaaaaatctgaaaacaggaaaatatgcaagaatgaggggtgcccacactaatgatgtaaaacaattaacagaggcagtgcaaaaaataaccacagaaagcatagtaatatggggaaagactcctaaatttaaactacccatacaaaaagaaacatgggaaacatggtggacagagtattggcaagccacctggattcctgagtgggagtttgtcaatacccctcccttagtaaaattatggtaccagttagagaaagaacccataataggagcagaaactttctatgtagatggggcagctaacagggagactaaattaggaaaagcaggatatgttactaacaaagggagacaaaaagttgtctccataactgacacaacaaatcagaagactgagttacaagcaattcttctagcattacaggattctggattagaagtaaacatagtaacagactcacaatatgcattaggaatcattcaagcacaaccagataaaagtgaatcagagatagtcagtcaaataatagagcagttaataaaaaaagaaaaggtctacctgacatgggtaccagcgcacaaaggaattggaggaaatgaacaagtagataaattagtcagtactggaatcaggaaagtactctttttagatggaatagataaagcccaagaagaacatgaaaaatatcacagtaattggagggcaatggctagtgattttaacctgccacctgtggtagcaaaagagatagtagccagctgtgataaatgtcagctaaaaggagaagccatgcatggacaagtagactgtagtccaggaatatggcaactagattgtacacatttagaaggaaaaattatcctggtagcagttcatgtagccagtggatatatagaagcagaagttattccagcagaaacagggcaggaaacagcatactttctcttaaaattagcaggaagatggccagtaaaaacagtacatacagacaatggcagcaatttcaccagtactacagttaaggccgcctgttggtgggcaggaatcaagcaggaatttggcattccctacaatccccaaagtcaaggagtagtagaatctataaataaagaattaaagaaagttataggacagataagagatcaggctgaacatcttaagacagcagtacaaatggcagtattcatccacaattttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaactaaagaactacaaaaacaaattacaaaaattcaaaattttcgggtttattacagggacagcagagatccactttggaaaggaccagcaaagcttctctggaaaggtgaaggggcagtagtaatacaagataatagtgacataaaagtagtgccaagaagaaaagcaaagatcattagggattatggaaaacagatggcaggtgatgattgtgtggcaagtagacaggatgaggattagaacatggaaaagtttagtaaaacaccatatgtatgtttcaaggaaagctaagggatggttttatagacatcactatgaaagtactcatccgagaataagttcagaagtacacatcccactagggaatgcaaaattggtaataacaacatattggggtctacatacaggagaaagagactggcatttgggtcaaggagtctccatagaattgaggaaaaggagatatagcacacaattagaccctaacctagcagaccaactaattcatctgcattactttgattgtttttcagaatctgctataagaaatgccatattaggacatatagttagccctaggtgtgaatatcaagcaggacataacaaggtaggatctctacagtacttggcactaacagcattagtaagaccaagaaaaaagataaagccacctttgcctagtgttacaaaactgacagaggatagatggaacaagccccagaagaccaagggccacaaagggaaccatacaatgaatggacactagaacttttagaggagctcaagaatgaagctgttagacattttcctaggatatggctccatagcttagggcaacatatctatgaaacttatggagatacttgggcaggagtggaagccataataagaattctgcaacaactgctgtttattcatttcagaattgggtgtcaacatagcagaatagacattcttcgacgaaggagagcaagaaatggagccagtagatcctagactagagccctggaagcatccaggaagtcagcctaggactgcttgtaccaattgctattgtaaaaagtgttgctttcattgccaagtttgtttcataacaaaaggcttaggcatctcctatggcaggaagaagcggagacagcgacgaagagctcctcaagacagtcagactcatcaagtttctctatcaaagcagtaagtagtacatgtaatgcaatctttacaaatattagcagtagtagcattagtagtagcagcaataatagcaatagttgtgtggtccatagtattcatagaatataggaaaataagaagacaaaacaaaatagaaaggttgattgatagaataatagaaagagcagaagacagtggcaatgagagtgacggagatcaggaagaattatcagcacttgtggaaatggggcacgatgctccttgggatgttaatgatctgtaaagctgcagaaaatttgtgggtcacagtttattatggggtacctgtgtggaaagaagcaaccaccactctattttgtgcctcagatgctaaagcgtatgatacagaggtacataatgtttgggccacacatgcctgtgtacccacagaccccaacccacaagaagtagaactgaagaatgtgacagaaaattttaacatgtggaaaaataacatggtagaccaaatgcatgaggatataattagtttatgggatcaaagcctaaagccatgtgtaaaattaaccccactctgtgttactttaaattgcactgattatgggaatgatactaacaccaataatagtagtgctactaaccccactagtagtagcgggggaatggaggggagaggagaaataaaaaattgctctttcaatatcaccagaagcataagagataaagtgaagaaagaatatgcacttttttatagtcttgatgtaataccaataaaagatgataatactagctataggttgagaagttgtaacacctcagtcattacacaggcctgtccaaaggtatcctttgaaccaattcccatacattattgtgccccggctggttttgcgattctaaagtgtaatgataaaaagttcaatggaaaaggaccatgtacaaatgtcagcacagtacaatgtacacatggaattaggccagtagtatcaactcaactgctgttaaatggcagtctagcagaagaagaggtagtaattagatcagacaatttctcggacaatgctaaagtcataatagtacatctgaatgaatctgtagaaattaattgtacaagactcaacaacattacaaggagaagtatacatgtaggacatgtaggaccaggcagagcaatttatacaacaggaataataggaaaaataagacaagcacattgtaacattagtagagcaaaatggaataacactttaaaacagatagttacaaaattaagagaacaatttaagaataaaacaatagtctttaatcaatcctcaggaggggacccagaaattgtaatgcacagttttaattgtggaggggaatttttctactgtaattcaacacaactgtttaacagtacttggaatggtactgcatggtcaaataacactgaaggaaatgaaaatgacacaatcacactcccatgcagaataaaacaaattataaacatgtggcaggaagtaggaaaagcaatgtatgcacctcccatcagaggacaaattagatgttcatcaaatattacagggctgatattaacaagagatggtggtattaaccagaccaacaccaccgagattttcaggcctggaggaggagatatgaaggacaattggagaagtgaattatataaatataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcaaagagaaaaaagagcagtgggaataataggagctatgctccttgggttcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagacaattattgtctggtatagtgcaacagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcacctcacagtctggggcatcaagcagctccaagcaagagtcctggctgtggaaagatacctaagggatcaacagctcctggggttttggggttgctctggaaaactcatttgcaccactgctgtgccttggaatactagttggagtaataaatctctgagtcagatttgggataacatgacctggatgcagtgggaaagggaaattgataattacacaagcttaatatacaacttaattgaagaatcgcaaaaccaacaagaaaagaatgaacaagagttattggaattagataactgggcaagtttgtggaattggtttagcataacaaattggctgtggtatataaaaatattcataatgatagtaggaggcttggtaggtttaagaatagtttttactgtactttctatagtaaatagagttaggcagggatactcaccattgtcgtttcagacgcgcctcccagccaggaggggacccgacaggcccgaaggaatcgaagaagaaggtggagagagagacagagacagatccggtcaattagtggatggattcttagcaattatctgggtcgacctgcggagcctgtgcctcttcagctaccaccgcttgagagacttactcttgattgtaacgaggattgtggaacttctgggacgcagggggtgggaagccctcaaatattggtggaatctcctacaatattggattcaggaactaaagaatagtgctgttagcttgctcaacgccacagccatagcagtagctgagggaactgatagggttatagaagtattacaaagagcttgtagagctattctccacatacctagaagaataagacagggcttagaaagggctttgcaataagatgggtggtaagtggtcaaaaagtagtaaaattggatggcctactgtaagggaaagaatgagaagagctgagccagcagcagatggggtgggagcagtatctcgagacctggaaaaacatggagcaatcacaagtagtaatacagcaactaacaatgctgattgtgcctggctagaagcacaagaggaggaggaggtgggttttccagtcagacctcaggtacctttaagaccaatgacttacaagggagcgttagatcttagccactttttaaaagaaaaggggggactggaagggctaatttggtcccagaaaagacaagacatccttgatttgtgggtccaccacacacaaggctacttccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggttggtgcttcaagctagtaccagttgagccagagaaggtagaagaggccaatgaaggagagaacaacagattgttacaccctgtgagcctgcatgggatggaggacccggagaaagaagtgttagtatggaggtttgacagccgcctagtactccgtcacatggcccgagagctgcatccggagtactacaaggactgctgacactgagctttctacaagggactttccgctggggactttccagggaggcgtggcctgggcgggactggggagtggcgagccctcagatgctgcatataagcagctgctttttgcctgtactgggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttca
Same "Sequence" - still different ...
We need to understand structure and function of proteins.
(Source: PDB)
Public Database content Experimentally determined protein structures (PDB)
214
1588
37'874
100
1,000
10,000
100,000
1,000,000
10,000,000
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
PDB
Public Database content Experimentally known protein structures (PDB)
100
1,000
10,000
100,000
1,000,000
10,000,000
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
SwissProt
PDB
Public Database content Annotated Protein Sequences: Swiss-Prot
100
1,000
10,000
100,000
1,000,000
10,000,000
1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006
TrEMBL
SwissProt
PDB
No experimentalstructure for mostprotein sequences
Public Database content Protein Sequences translated from DNA: trEMBL
(Sources: PDB, EBI, SIB)
The protein sequence contains all information needed to create a correctly folded protein (Anfinsen principle).Can we model protein structures from their protein sequences?
Many proteins fold spontaneously to their native structure Protein folding is relatively fast (nsec – sec) Chaperones speed up folding, but do not alter the structure
MNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITKDEAEKLFNQD VDAAVRGILR NAKLKPVYDS LDAVRRCALI NMVFQMGETG VAGFTNSLRMLQQKRWDEAA VNLAKSRWYN QTPNRAKRVI TTFRTGTWDA YKNL
Protein Folding
Comparative protein structure modelling
René Magritte. The Human Condition. 1935. Oil on canvas.
Known Structures(Templates)
Target Sequence Template Selection
Alignment Template - Target
Structure modeling
Structure Evaluation & Assessment
HomologyModel(s)
Comparative Protein Structure Modelling
Comparative Protein Structure Modelling
Why do we need automated expert systems for comparative protein modelling?
Too many new sequences, too many new structures
Objectivity and Reproducibility: remove individual human bias;
predictable reliability of results
Improve methods and algorithms
Easy access for “end users”
User emails ...
To: <[email protected]>From: Karin Schwarz <[email protected]>
Dear Mr. Schwede,
I am looking for firms, which needs also models with a high from 168 cm. Do you need someone?
Best regards
K. Schwarz
ExPASY
Biozentrum, SIB (Basel) & NCI (ABBC)
PDB Database-> SMTL
SwissProt/TrEMBL
RCSB
EBI
NR / Blast NCBI
How to automate protein modeling?
Target Sequence
Known Structures(Templates)
Template Selection
Alignment Template - Target
Structure modeling
Structure Evaluation &Assessment
HomologyModel(s)
3D - Model requests:
2005: >148’000 requests
~ 400 models per work day~ one model every 4 minutes
SWISS-MODEL Server
1. M.C. Peitsch and C.V. Jongeneel (1993) Int. Immunol. 5, 233-2382. Peitsch MC (1995) Bio/Technology 13:658-660. 3. Guex N and Peitsch MC (1997) Electrophoresis 18:2714-2723.4. Schwede T, Kopp J, Guex N, Peitsch MC (2003) Nucleic Acids Research 31, 3381-3385.
SWISS-MODEL Workspace
Arnold K, Bordoli L, Kopp J, Schwede T (2006) Bioinformatics 22,195-201.
SWISS-MODEL Template Library
Arnold K, Bordoli L, Kopp J, Schwede T (2006) Bioinformatics 22,195-201.
[ http://www.expasy.org/spdbv/ ]
Collaboration withNicolas Guex (GSK)
DeepView - Swiss-PdbViewer
Guex N and Peitsch MC (1997) Electrophoresis 18:2714-2723.
SwissProt / TrEMBL
SWISS-MODELRepository
Oracle Control DB
Qualityok?
PDB/SMTL
Sequence updates
Template updates
SWISS-MODELServer
UpdateModel?
SWISS-MODELRepository
mySQL DB / WEB
Image Rendering Server
Coordinate Repository Server
Computational Services e.g. Anolea quality control
Reverse Proxy Services
CRC64
SWISS-MODEL Repository
Kopp J, and Schwede T (2004). Nucleic Acids Research 32 , D230-D234.
SWISS-MODEL Repository
Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.
SWISS-MODEL Repository
Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.
SWISS-MODEL Repository
Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.
Evaluation of Model Accuracy
SIV Model based on: 1BL3 (C) HIV-1 Integrase core domainExperimental structure: 1C6V (C) SIV Integrase core domainSeq. Identity: 61 %
“... a model must be wrong, in
some respects -- else it would be the thing itself. The trick is to see ... where it is right.”
Evaluation of model accuracy
Henry A. Bent"Uses (and Abuses) of Models in Teaching Chemistry," J. Chem. Ed. 1984 61, 774.
Evaluation of Model Accuracy
CASPCommunity Wide Experiment on the Critical Assessment of Techniques for Protein Structure Predictionhttp://PredictionCenter.org
EVA Evaluation of Automatic protein structure prediction http://eva.compbio.ucsf.edu/~eva/
(Koh et al. (2003) Nucleic Acids Res. 31, 3311-5 )
3D - Crunch ExperimentVery Large Scale Protein Modelling Project (1998) http://www.expasy.org/swissmod/SM_LikelyPrecision.html
Weekly PDB released target sequencesMNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITK
EVA Server Prediction Servers
e.g. SWISS-MODEL
1
Evaluation of automated protein structure prediction
(Koh et al. (2003) Nucleic Acids Res. 31, 3311-5 )
2 Predicted structure
Evaluation of prediction accuracy
3
Does the model have the correct fold? What would have been the best template? What would have been the best alignment? How difficult was the modeling?
Alignment accuracy Overall accuracy (RMSD)
core regions loop regions side chain rotamer
Stereo-chemical quality of the model
MNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITK
Evaluation of Automated protein structure prediction
[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]
The analysis of ~1 year of models for all PDB
released structures is necessary for a
statistically relevant comparison of modelling
methods.
Evaluation of 246 weekly PDB releases (20'108 models)
Evaluation of Automated protein structure prediction
Evaluation of 246 weekly PDB releases (20'108 models)
[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]
SWISS-MODEL has the lowest
cumulative average global RMSD of the
servers in the comparison.
Evaluation of Automated protein structure prediction
[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]
The lower RMSD of SWISS-
MODEL is related to a
lower coverage in sequence
space.
Evaluation of 246 weekly PDB releases (20'108 models)
Save Zone
TwilightZone
MidnightZone
Evaluation of Model Accuracy
[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]
Applications of comparative modelling
Possible applications of comparative models depend on the expected accuracy.
(Kopp & Schwede, Pharmacogenomics, 2004 )
Application Examples
Structural Assessment of Sequence VariationsComparative modeling allows for detailed structure-based assessment of sequence variations. Mutations, ns-cSNPs, alternative splicing, iso-forms and other sequence variations may be responsible for functional variations and involved in rare inherited diseases, individual differences in drug response, and susceptibility for common diseases.
(Wattenhofer, et. al. J. Mol. Med. 2002 )
Applications:
Rational design of Functional MutationsComparative modeling allows for designing specific site directed mutations
to study functional role of individual residues or structural features.
Example: Design of partial and complete deletion mutations of the plug
domain of Sec61p to study its functional role. Conclusion: The plug domain
of Sec61p is non-essential, but influences topogenesis and Sec61 assembly.
Junne, Schwede, Goder & Spiess (2006) Molecular Cell, in press
Application: Models in structure based drug discovery
Can homology models be used in structure based drug discovery when no experimental protein structures are available?
How do errors and inaccuracies of the homology models affect the subsequent molecular modeling of protein-ligand interaction?
Estimating relative ligand binding free energies using MD-GBSA
500 ps MD Simulation for conformational sampling (MM-GBSA)∆Gbind = < ∆Evacuo > + < ∆Gdesolv > - < T∆S >
Collaboration with Markus Meuwly (Computational Chemistry, Uni Basel) & Vincent Zoete (SIB Lausanne)
Thorsteinsdottir HB, Schwede T, Zoete V, and Meuwly M (2006). Proteins (in press).
Example: 16 HIV-I protease inhibitor complexes Validation: Correlation between experimental and
calculated relative binding free energies Application: Systematic analysis of the influence of typical
modeling errors.
Application: Models in structure based drug discovery
Reference1HVI
relative Gcalculated
Reference Model:All ligands computed in 1HVI as reference structure
HM based onEIAV
Rotamer model
relative Gcalculatedrelative Gcalculated
Twilight Zone Model:based on Equine infectious anemia virus protease (1FMB) sharing 32% seq. id.RMSD (5 Å of ligand) 1.30 Å
SCWRL Rotamer Model:Rotamers of reference structure remodelled using SCWRL3.0.1
RMSD (5 Å of ligand) 1.26 Å1 SCWRL3.0 (A. A. Canutescu, A. A. Shelenkov, and R. L. Dunbrack, Jr. Protein Science 12, 2001-2014 (2003). Thorsteinsdottir HB, Schwede T, Zoete V, and Meuwly M (2006). Proteins (in press).
Summary and Outlook
Summary and outlook
Today's Bioinformatics view is still largely (DNA)- sequence centric. Understanding macromolecular function in detail requires knowledge of its 3D structure.
10 years ago, for the vast the majority of proteins no information about its 3-dimensional structure was available.
Today, structural genomics and comparative modelling are complementing each other in exploring the structural space. Within the next decade, 3D information will become available for the majority of all globular protein domains.
> 90 % of this structural information will be based on comparative models.
SWISS-MODEL aims at providing a fully integrated protein-centric view of all available structural information on a given protein.
SWISS-MODEL is accessible freely at Expasy:
SWISS-MODEL
SWISS-MODEL Server: http://swissmodel.expasy.org
DeepView (Swiss-PdbViewer) http://www.expasy.org/spdbv/
SWISS-MODEL Workspace: http://swissmodel.expasy.org/workspace/
SWISS-MODEL Repository: http://swissmodel.expasy.org/repository/
Biozentrum & SIB BaselHólmfríður B. ÞorsteinsdóttirLorenza BordoliJürgen KoppMichael PodvinecJames BatteyKonstantin ArnoldRainer PöhlmannRoger JenniRobert GaisbauerMihaela ZavolanMartin Spiess
University of BaselMarkus Meuwly
Novartis BaselManuel Peitsch
SIB - Swiss Institute of Bioinformatics (LS & GE) Amos BairochElisabeth GasteigerErnest FeytmansOlivier MichielinVincent ZoeteVictor JongeneelJacques Rougemont
NCI FrederickJack CollinsKarol Miaskiweicz Robert W. Lebherz
GSK R&DNicolas GuexAlexander Diemand Financial support:
EBI - European Bioinformatics InstituteKim HenrickRolf ApweilerNicola MoulderUjjwal Das
Pontificia Universidad Católica de Chile Francisco Melo
Acknowledgements
Biozentrum & SIB BaselHólmfríður B. ÞorsteinsdóttirLorenza Bordoli Jürgen KoppMichael PodvinecJames BatteyKonstantin ArnoldRainer PöhlmannRoger JenniRobert GaisbauerMihaela ZavolanMartin Spiess
University of BaselMarkus Meuwly
Novartis BaselManuel Peitsch
SIB - Swiss Institute of Bioinformatics (LS & GE) Amos BairochElisabeth GasteigerErnest FeytmansOlivier MichielinVincent ZoeteVictor JongeneelJacques Rougemont
NCI FrederickJack CollinsKarol Miaskiweicz Robert W. Lebherz
GSK R&DNicolas Guex Alexander Diemand Financial support:
EBI - European Bioinformatics InstituteKim HenrickRolf ApweilerNicola MoulderUjjwal Das
Pontificia Universidad Católica de Chile Francisco Melo
Acknowledgements