3d -coffee mixing sequences and structures
DESCRIPTION
3D -COFFEE Mixing Sequences and Structures. Cédric Notredame. Potential Uses of A Multiple Sequence Alignment ?. chite ---ADKPKRPLSAYMLWLNSARESIKRENPDFK-VTEVAKKGGELWRGLKD wheat --DPNKPKRAPSAFFVFMGEFREEFKQKNPKNKSVAAVGKAAGERWKSLSE trybr KKDSNAPKRAMTSFMFFSSDFRS----KHSDLS-IVEMSKAAGAAWKELGP - PowerPoint PPT PresentationTRANSCRIPT
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3D-COFFEE Mixing Sequences and Structures
Cédric Notredame
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chite ---ADKPKRPLSAYMLWLNSARESIKRENPDFK-VTEVAKKGGELWRGLKDwheat --DPNKPKRAPSAFFVFMGEFREEFKQKNPKNKSVAAVGKAAGERWKSLSEtrybr KKDSNAPKRAMTSFMFFSSDFRS----KHSDLS-IVEMSKAAGAAWKELGPmouse -----KPKRPRSAYNIYVSESFQ----EAKDDS-AQGKLKLVNEAWKNLSP ***. ::: .: .. . : . . * . *: *
chite AATAKQNYIRALQEYERNGG-wheat ANKLKGEYNKAIAAYNKGESAtrybr AEKDKERYKREM---------mouse AKDDRIRYDNEMKSWEEQMAE * : .* . :
Potential Uses of A Multiple Sequence Alignment?
Extrapolation
Motifs/Patterns
Phylogeny
Profiles
Struc. PredictionMultiple Alignments Are CENTRAL to MOST Bioinformatics Techniques.
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Why Is It Difficult To Compute A multiple Sequence Alignment?
A CROSSROAD PROBLEMBIOLOGY:
What is A Good Alignment
COMPUTATIONWhat is THE Good
Alignment
chite ---ADKPKRPLSAYMLWLNSARESIKRENPDFK-VTEVAKKGGELWRGLKDwheat --DPNKPKRAPSAFFVFMGEFREEFKQKNPKNKSVAAVGKAAGERWKSLSEtrybr KKDSNAPKRAMTSFMFFSSDFRS----KHSDLS-IVEMSKAAGAAWKELGPmouse -----KPKRPRSAYNIYVSESFQ----EAKDDS-AQGKLKLVNEAWKNLSP ***. ::: .: .. . : . . * . *: *
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Why Is It Difficult To Compute A multiple
Sequence Alignment ?
BIOLOGY
CIRCULAR PROBLEM....
GoodSequences
GoodAlignment
COMPUTATION
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The T-Coffee Algorithm
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Local Alignment Global Alignment
Extension
Multiple Sequence Alignment
Mixing Local and Global Alignments
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What is a library?
Extension+T-Coffee
Library Based Multiple Sequence Alignment
2Seq1 MySeqSeq2 MyotherSeq#1 21 1 253 8 70….
3Seq1 anotherseqSeq2 atsecondoneSeq3 athirdone#1 21 1 25#1 33 8 70….
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The Triplet Assumption
X
Y
Z
X
Y
SEQ A
SEQ B
Consistency Consensus
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ClustalW T-Coffee
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Dynamic Programming Using An Extended Library
Progressive Alignment
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What Is BaliBaseHow Good is T-Coffee ???
Best Performing Method on MSA benchmark Datasets
BaliBase -Notredame-Sonhammer
Ribosomal RNA-Katoh (Mafft)
Homstrad-Notredame
OxBench-Barton
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Mixing Heterogenous Data With
T-CoffeeLocal Alignment Global Alignment
Multiple Sequence Alignment
Multiple Alignment
StructuralSpecialist
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Mixing Sequences and Structures
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Why Do We Want To Mix Sequences and Structures?
1-Predicting Sequence Structures
STUCTURE FUNCTION
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Why Do We Want To Mix Sequences and Structures?
•Sequences are Cheap and Common.
•Structures are Expensive and Rare.
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Why Do We Want To Mix Sequences and Structures?
Cheapest Structure determination:
Sequence-Structure Alignment
THREADOr
ALIGNADKPRRP---LS-YMLWLNADKPKRPKPRLSAYMLWLN
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Why Do We Want To Mix Sequences and Structures?
ADKPRRP---LS-YMLWLNADKPKRPKPRLSAYMLWLN
THREADOr
ALIGN
Convincing Alignment
Same Fold
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Why Do We Want To Mix Sequences and Structures?
Convincing Alignment
Same Fold
Distant sequences are hard to align
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Why Do We Want To Mix Sequences and Structures?
chite ---ADKPKRPLSAYMLWLNSARESIKRENPDFK-VTEVAKKGGELWRGLKDwheat --DPNKPKRAPSAFFVFMGEFREEFKQKNPKNKSVAAVGKAAGERWKSLSEtrybr KKDSNAPKRAMTSFMFFSSDFRS----KHSDLS-IVEMSKAAGAAWKELGPmouse -----KPKRPRSAYNIYVSESFQ----EAKDDS-AQGKLKLVNEAWKNLSP ***. ::: .: .. . : . . * . *: *
Multiple Sequence Alignments Help
Exploring the Twilight Zone
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Why Do We Want To Mix Sequences and Structures?
1-Predicting Sequence Structures
2-Produce Better Alignments
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Why Do We Want To Mix Sequences and Structures?
ADKPRRP---LS-YMLWLNADKPKRPKPRLSAYMLWLNALIGN
Unreliable alignment if %ID <30%
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Why Do We Want To Mix Sequences and Structures?
Alignment Unsentitive to %ID
ADKPRRP---LS-YMLWLNADKPKRPKPRLSAYMLWLN
Struc.Superposition
Folds evolve Slower than Sequences
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Why Do We Want To Mix Sequences and Structures?
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Why Do We Want To Mix Sequences and Structures?
StructureSuperposition
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Why Do We Want To Mix Sequences and Structures?
1-Predicting Sequence Structures
2-Produce Better Alignments
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How To Mix Sequences and
Structures
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Mixing Heterogenous Data With
T-CoffeeLocal Alignment Global Alignment
Multiple Sequence Alignment
Multiple Alignment
StructuralSpecialist
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Struct Vs StructSeq Vs Struct
Thread
Evaluation on Homestrad
Superpose
Seq Vs SeqLocalGlobal
Mixing Sequences and Structures with T-Coffee
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The 3D-Coffee LibrariesMethods
•Global: Needlman and Wunsch
•Local: Sim (lalign)
•Threading: Fugue
•Superposition:SAP
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•Threading: Fugue
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Fugue
•Threading: Fugue
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Fugue
•Threading: Fugue
1-Turn Sequence into a profile:-lower penalties in loops-Structure specific matrix
2-Align Profile
withSequence
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Evaluating Fugue
•Threading: Fugue
1-Select 967 pairs of sequences in HOMSTRAD
FUGUE T-Coffee2-Align each pair with T-Coffee and Fugue.
Compare
3-Compare the TwoAlignments
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Fugue
•Threading: Fugue
1-Select 967 pairs of sequences in HOMSTRAD
2-Align each pair with T-Coffee and Fugue.
3-Compare the TwoAlignments TCdef wins
Fugue wins TCdef: 58.81%Fugue: 61.81%
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Superposition:
SAP
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•Superposition:SAP
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•Superposition:SAP
1-High Level Dynamic Programming
Substitution Matrix when doing regular Alignments
2-Low Level DP.Forcing the aln of two residues
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1-High Level Dynamic Programming
•Superposition:SAP
1
9
12131
8
14
53-Rigid Body Superposition
RMSD
2-Low Level DP.Forcing the aln of two residues
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1-High Level Dynamic Programming
•Superposition:SAP
1
9
1213
18
14
53-Rigid Body Superposition
RMSD2-Low Level DP.Forcing the aln of two residues
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1-High Level Dynamic Programming
•Superposition:SAP
3-Rigid Body Superposition
2-Low Level DP.Evaluate Every Pair
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1-High Level Dynamic Programming
•Superposition:SAP
Structure Based Sequence Alignment
Make a DP on the
accumulated traces
Use Traces like a
Substitution Matrix
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SAP T- Coff ee
Compare
1-Select 967 pairs of sequences in HOMSTRAD
2-Align each pair with T-Coffee and SAP.
3-Compare the TwoAlignments
•Superposition:SAP
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1-Select 967 pairs of sequences in HOMSTRAD
2-Align each pair with T-Coffee and SAP.
3-Compare the TwoAlignments
•Superposition:SAP
TCdef: 58.81%SAP: 86.31%
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•SAP•Fugue
TCdef: 58.81%Fugue: 61.81%
TCdef: 58.81%Fugue: 86.31%
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Sequences and Structures:
How Good is The Mixture ???
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Our Benchmark:
HOM39
-HOMSTRAD: Structure based MSAs that can be used as References.
-COMPACT and DEMANDING
-HOM39: The 39 Most difficult datasets (percent ID lower than 25).
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Our BenchMark:
Using HOM39
BENCHMARKING Strategy:
-re-align HOM39 without using ALL the structures
-Compare the result with the reference
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Evaluating 3D-Coffee
1- Can a SINGLE structure Help ?
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Seq Vs Struct
Thread
Evaluation on HOM39
Seq Vs SeqLocalGlobal
Using ONE structure with3D-Coffee
HOM39 with ONE Structure per MSA
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Evaluating 3D-Coffee
1- Can a SINGLE structure Help ?
2- Does it benefit to ALL the Sequences
Is EVERYONE Happier if there is a STAR in the team…
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BaliBase
HOM39 TC-Fugue
+
Remove Provided Structure(s)
Comparison
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Evaluating 3D-Coffee
1- Can a SINGLE structure Help ?
3- Can We Use Two or More Structures
2-Does it benefit to all the sequences
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Seq Vs Struct
Fugue
Evaluation on Homestrad
Seq Vs SeqLocalGlobal
Mixing Sequences and Structures with 3D-Coffee
HOM39 with TWO Structures/MSA
Struct Vs Struct
SAP, LSQ
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Indirect Improvement
Direct Improvement
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Evaluating 3D-Coffee
1- Can a SINGLE structure Help ?
4-Relation Accuracy/ N-structures ???
2-Does it benefit to all the sequences
3-Can we use Two Structures
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Seq Vs Struct
Fugue
Evaluation on Homestrad
Seq Vs SeqLocalGlobal
Mixing Sequences and Structures with T-Coffee
HOM39 with 1-N Structures per MSA
Struct Vs Struct
SAP
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Induced Improvement
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Conclusion
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-Structures Help
BUT NOT SO MUCH
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The More Structures The Merrier
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The More Structures The Merrier
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Credits
Orla O’Sullivan: University College, Cork, Ireland
Des Higgins: University College, Cork, Ireland
Karsten Suhre: IGS-CNRS, Marseille, France
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