Presentazione di PowerPoint

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From sequence to structure to function future
or fantasy?
1st International Symposium on Biological and
Medical Data Analysis
Anna Tramontano
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• Structure prediction methods
• Observed and expected accuracy
• Future perspectives

Outline
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Molecular function
The paradigm
Molecular structure
Sequence
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• Comparative modeling
• based on evolution
• Fold recognition
• based on fold recurrence
• New folds

Structure prediction methods
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Structure prediction methods Comparative
modeling
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r.m.s.d. (1/N S d2)1/2
Structure prediction methods Comparative
modeling
Fraction sequence identity after structural
superposition
Chothia and Lesk, EMBO J., 1986
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AVGIFRAAVCTRGVAKAVDFVP

AVGIFRAAVCTRGVAKAVDFVP
AIGIWRSATCTKGVAKA--FVA
Structure prediction methods Comparative
modeling
If the alignment is correct, we can use the
Chothia and Lesk relationship to predict the
expected quality of the model
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The best methods construct several initial models
for the protein
Structure prediction methods Comparative
modeling
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• Comparative modeling
• based on evolution
• Fold recognition
• based on fold recurrence
• New folds

Structure prediction methods
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Structure prediction methods Fold recognition
Score and select model
Orengo, Curr. Op. Str. Biol, 1994
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• Comparative modeling
• based on evolution
• Fold recognition
• based on fold recurrence
• New folds

Structure prediction methods
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AVGIFRAAVCTRGVAKAVDFVP
AVGIFR
AAVCTR
GVAKAVDF
Structure prediction methods New folds
Bystroff and Baker, JMB, 1998
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AVGIFRAAVCTRGVAKAVDFVP
AVGIFR
AAVCTR
GVAKAVDF
Structure prediction methods New folds
Bystroff and Baker, JMB, 1998
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AVGIFRAAVCTRGVAKAVDFVP
AVGIFR
AAVCTR
GVAKAVDF
Structure prediction methods New folds
Bystroff and Baker, JMB, 1998
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AVGIFRAAVCTRGVAKAVDFVP
AVGIFR
AAVCTR
GVAKAVDF
Structure prediction methods New folds
Bystroff and Baker, JMB, 1998
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AVGIFRAAVCTRGVAKAVDFVP
AVGIFR
AAVCTR
GVAKAVDF
Structure prediction methods New folds
Score and select model
Bystroff and Baker, JMB, 1998
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CASP Critical assessment of techniques for
protein structure prediction
Structure prediction evaluation
Moult et al., Proteins, 1995
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Targets
Groups
Structure prediction evaluation
Models
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CASP5
Structure prediction evaluation
Tramontano and Morea, Proteins, 2002
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Is there progress?
CASP4 and CASP5 Best models
120.00
100.00
80.00
Structure prediction methods Alignment accuracy
max AL0
60.00
40.00
20.00
0.00
0
10
20
30
40
50
60
id
Cozzetto and Tramontano, Proteins, in press
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Structural genomics
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Structural genomics
If the alignments are correct, these two protein
structures are expected to be predicted with
equivalent accuracy
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14
26
31
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Structure prediction methods Alignment accuracy
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14
12
Template
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Target
30
23
15
20
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Cozzetto and Tramontano, Proteins, in press
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Which is the most difficult pair-wise alignment
that we need to carry out?
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24
14
26
31
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Structure prediction methods Alignment accuracy
18
14
12
Template
10
Target
30
23
15
20
31
m 25
Cozzetto and Tramontano, Proteins, in press
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CASP4 and CASP5 Best models
Structure prediction methods Alignment accuracy
Cozzetto and Tramontano, Proteins, in press
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CASP4 and CASP5 Best models
Structure prediction methods Alignment accuracy
Cozzetto and Tramontano, Proteins, in press
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• CASP is known for the assessment of structure
  prediction but it also assesses
• Domain prediction
• Disorder prediction
• Contact prediction
• Function

Function prediction category
Soro and Tramontano, in progress
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59 targets
Function prediction category
Soro and Tramontano, in progress
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59 targets
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40
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Function prediction category
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10
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Medline
Swissprot
Pfam
??
Soro and Tramontano, in progress
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Will the knowledge of the experimental structure
affect the predictions?
Function prediction category
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Krzysztof Fidelis Tim Hubbard Andriy
Kryshtafovych John Moult Burkhard Rost Adam
Zemla Structural biologists Predictors Tiziana
Castrignano
Claudia Bonaccini Domenico Cozzetto Veronica
Morea Romina Oliva Simonetta Soro Raphael
Leplae Elisabetta Pizzi Raffaele De
Francesco Asutosh Yagnik

Acknowledgements
BioSapiens - EU VI Framework Ministero della
Salute Universita' di Roma Istituto Pasteur Roma
Facolta' di Medicina San Paolo CNR