integración de datos evolutivos en la predicción de estructura y función

Alfonso Valencia CNB-CSIC

Integración de datos evolutivosen la predicción de estructura y función

Alfonso Valencia

CNB - CSIC


ranrcc1

by J.A. G-Ranea


Cluster of solutions 1 Cluster of solutions 2

Solution 3 Solution 4

by J.A. G-Ranea


Ras

Ral

Rho

RasRalRho

ranrcc1

by J.A. G-Ranea


Model

Mapping of tree determinants


Azuma et al., J,Mol. Biol. 1999


Model

D44GDPMg++

H270

R206

H304

E157

D128H78

H410

Green: Km, red: Kcat.

Mapping of mutants (side view)


Complex

Ran

SO4

Rcc1

Model and Xray

Model

Ran

Mg++GDP

Rcc1


13

59

3

122

GRAMM results

Ran (GDP-Mg++)Rcc1

Ran (SO4)Rcc1

Complex/Docking superposition

Model/Docking superposition

Complex:

Model:


Complex(Model on Vomplex superposition)

Model

GDP

Mg++

D44

H78

D128

E157

R206

H270

H304

H78

H78

H410

D44GDPMg++

H270

R206

H304

E157

D128H78

H410

Green: Km, red: Kcat.

Mapping of mutants (side view)


Complex Model

Mapping of tree determinants


Ras Binding Domain foldingRas

Rlip (coiled-coil)Ral

Functional specificity in the ras superfamily

By J.A. Ranea


The space of sequences

Yeast Two-Hybrid Experiments (Bauer et. al. JBC 1999)

by J.A. G-Ranea

Ras

Ral

Rho

RasRalRho

Sequencespace(Casari, Sander, Valencia, Nature. Str. Bio. 95)

36 and 37 maintree-determinant

positions


DnaK

FtsA

Actin

Hexokinase

Hsc70

MreB


Mirror - trees

proteindistancematrices

d1

d2

Caa Cbb Cab

0.0

+1.0

correlation values distributions

In silico 2 hybrid

prot. a prot. borg. 1

org. 1org. 2 org. 2org. 3 org. 3org. 4

org. 4org. 5

org. 5

intra-protein inter-protein

intra- and inter-protein correlatedmutations

interaction index between a and b

r: similarity between a and b trees

multiple sequence alignments(MSA)

reducedMSAs& implicittrees

reducedMSAs


A dimerization model for FtsA

1 MIKATDRKLVVGLE IGTAKVAALVGEVLPDGMVN IIGVGS 40 41 CP SRGMD KGGVNDLESVVKCVQR AIDQA ELMADCQISSV Y 80 81 LALSGK HISCQNEIGMVPISEEEVTQEDVENVVHTAKSVR 120121 VRDEH RVLHVIPQ EYAI DYQEGIKNPV GLSGVRMQ AKVHL 160161 ITCHNDMAKNIVKAVERCGLKVDQLIFAGLA SSYSVLTED 200201 ERELGVCVVDIG GGTMDIAVYTGGALRHTKVIPYA GNVVT 240241 S DIAYAFGTPPSDAEAIKVRHGCALGSIVGKDESVEVPSV 280281 GGRPPRSLQRQTLAEVIEP RYT ELLNLVNEEILQLQEKLR 320321 QQGVKHHLAAGIV LTGGAAQIEGLAACAQRVFHTQVRIGA 360361 PLNITGLTDYAQEPYYSTAVGLLHYGKESHLNGEAEVEKR 400401 VTASVGSWIKRLNSWLRKEF 420

Carettoni, et al., (2002) Phage-display and correlated mutations identify an essential region of subdomain 1C involved in homodimerization of Escherichia coli FtsA Proteins

Löwe et al., Nature 00


Information extracted from multiple sequence alignments

Ras

Ral

Rho

Correlated mutations Tree-determinant

conserved


Prediction of interaction regions

AV..WY

aa.

..... .....

.....

InterfaceNo

5,6,10,20,22,30

5 6 10 20 22 30

3D str.Surface patch

Sequenceprofiles

Multiplesequencealignment

Fariselli, et al., (2002). Prediction of protein-protein interaction sites with neural networks. Eur J Biochem


Prediction of protein interaction sites with neural networks

Goal: Predict surface residue in contact with another protein.

Method: Feed-forward neural network trained with standard back-propagation.

Output layer: Single neuron representing contact / no contactHidden layer: 4 nodesInput layer:

- Patches in protein structures (sets of exposed neighbour residues)

11 residue-long window, central surface residue + 10 patch neighbours

- Evolutionary informationResidue coded as a vector corresponding to frequencies in

the MSA

Result: 73% average accuracy of correctly predicted interacting residues

Fariselli, Pazos,Valencia, Casadio, Eur. J. Biochem. 02


Results of the predictions of protein interaction sites



NN predictions of interaction regions

A B



Mirror - trees

proteindistancematrices

d1

d2

Caa Cbb Cab

0.0

+1.0

correlation values distributions

In silico 2 hybrid

prot. a prot. borg. 1

org. 1org. 2 org. 2org. 3 org. 3org. 4

org. 4org. 5

org. 5

intra-protein inter-protein

intra- and inter-protein correlatedmutations

interaction index between a and b

r: similarity between a and b trees

multiple sequence alignments(MSA)

reducedMSAs& implicittrees

reducedMSAs


DnaK

FtsA

Actin

Hexokinase

Hsc70

MreB


Prediction of interaction regions

AV..WY

aa.

..... .....

.....

InterfaceNo

5,6,10,20,22,30

5 6 10 20 22 30

3D str.Surface patch

Sequenceprofiles

Multiplesequencealignment

Fariselli, et al., (2002). Prediction of protein-protein interaction sites with neural networks. Eur J Biochem


Prediction of protein interaction sites with neural networks

Goal: Predict surface residue in contact with another protein.

Method: Feed-forward neural network trained with standard back-propagation.

Output layer: Single neuron representing contact / no contactHidden layer: 4 nodesInput layer:

- Patches in protein structures (sets of exposed neighbour residues)

11 residue-long window, central surface residue + 10 patch neighbours

- Evolutionary informationResidue coded as a vector corresponding to frequencies in

the MSA

Result: 73% average accuracy of correctly predicted interacting residues



Results of the predictions of protein interaction sites



A dimerization model for FtsA

1 MIKATDRKLVVGLE IGTAKVAALVGEVLPDGMVN IIGVGS 40 41 CP SRGMD KGGVNDLESVVKCVQR AIDQA ELMADCQISSV Y 80 81 LALSGK HISCQNEIGMVPISEEEVTQEDVENVVHTAKSVR 120121 VRDEH RVLHVIPQ EYAI DYQEGIKNPV GLSGVRMQ AKVHL 160161 ITCHNDMAKNIVKAVERCGLKVDQLIFAGLA SSYSVLTED 200201 ERELGVCVVDIG GGTMDIAVYTGGALRHTKVIPYA GNVVT 240241 S DIAYAFGTPPSDAEAIKVRHGCALGSIVGKDESVEVPSV 280281 GGRPPRSLQRQTLAEVIEP RYT ELLNLVNEEILQLQEKLR 320321 QQGVKHHLAAGIV LTGGAAQIEGLAACAQRVFHTQVRIGA 360361 PLNITGLTDYAQEPYYSTAVGLLHYGKESHLNGEAEVEKR 400401 VTASVGSWIKRLNSWLRKEF 420


Löwe et al., Nature 00


NN predictions of interaction regions

A B



Carnitine Acyl transferases

2dubE/CPTI/COT/CACP

P. Gomez-Puertas / F. G. Hegardt lab

Carnitine OctanoyltransferaseCarnitine Palmitoyltransferase I

Octanoyl-CoA

Malonyl-CoA

A332

H327(catalytic)

A478

Palmitoyl-CoA

Malonyl-CoA

H473(catalytic)

Morillas et al. 2001. J.Biol.Chem. 276, 45001-8, 2001 in the press, and 2002 in the press


Protein Design Group CNB-CSIC

David de JuanProtein interactions

Damien DevosFunction prediction at genomic scale

Rita CasadioPierro FariselliU. Bologna

Antoine de DaruvarLion, Heidelberg.

Burkhard RostColumbia U., NY

Søren BrunakDTU, Copenhagen

Christos OuzounisEBI-EMBL, Cambridge

Julio Collado-VidesUNAM, Cuernavaca.

María GonzálezGenomics, Ecology

Ramón AlonsoArabidopsis T. factors

Juan Antonio G. Ranearas signalling system

Protein Design

RASRASE. Laue, CambridgeE. Laue, CambridgeF. Wittinghoer, MPIF. Wittinghoer, MPI

Andrés Moya,Roeland van Ham U. Valencia

Centro de Astrobiología

Federico AbascalFunction prediction

CICYTCICYTbiotechbiotech

Protein Structure Prediction

CICYTCICYTFEDERFEDER

www.pdg.cnb.uam.es

DNA arrays

EC V FPEC V FP

Manuela Helmer-CitterichU. TorVergata,

Paulino Gómez PuertasBacterial Cell Division

Luis Sánchez-PulidoSequence analysis

Ramón RocaHomology modeling

SANITASSANITASMiguel VicenteMiguel VicenteCNB - CSICCNB - CSIC

Osvaldo GrañaThreading / servers

ALMA Bioinformática S.L.

Armando AmatSystem management

Bioinformatics support

Information extraction

Florencio PazosInteraction networks

Keith Harshman,Carlos MartínezD I O - C N B

Genome analysis

Amalia Muñozbinding specificity system

Juan Carlos SanchezTFs in Aspergilus

Enrique MerinoCentro Bioitecnología UNAM, Cuernavaca

Javier GuijarroInteraction networks

Manuel GómezBacterial Cell division II

Prof. Hans Robert KalbitzerU. Regensburg

Visitors

José María FernandézDatabase design

REGIAREGIAJ. Pazares, CNB-J. Pazares, CNB-CSICCSIC

SH3SH3B. Distel, AmsterdamB. Distel, Amsterdam

Ugo BastollaProtein stability

Fausto EdgarthU. Barcelona

Michael TressThreading

Juan Carlos Oliveros Array data management

Roderic GuigoIMIM, Barna

Joaquin DopazoJavier HerreroCNIO

Javier TamamesGenome analysis

TEMBLOTEMBLORREBIEBIEC VFPEC VFP

Robert HoffmannI.E. Biomedicine

ORIELORIELEMB0EMB0EC VFPEC VFP

InformationExtraction

Christian BlaschkeInformation extraction

Eduardo LeonDetection of protein names

Systems

Miguel A. PeñalvaCIB-CSIC


Protein interactions

Text miningBiological examples

integración de datos evolutivos en la predicción de estructura y función

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