docking de proteínas -...
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BIOINFORMBIOINFORMÁÁTICA Y BIOLOGTICA Y BIOLOGÍÍA COMPUTACIONALA COMPUTACIONALCursoCurso de de veranoverano de la Universidad de la Universidad ComplutenseComplutense (Julio 2008)(Julio 2008)
Docking de Docking de ProteProteíínasnas
Juan Juan FernFernáándezndez RecioRecioBarcelona Supercomputing Barcelona Supercomputing CenterCenter (BSC)(BSC)
•• IntroductionIntroduction• Computational protein-protein docking
• Geometric docking algorithms
• Docking by global energy optimization
• Comparison of docking methods
• Docking applications and future challenges
- two-hybrid test- affinity column, gel assays...- BIAcore- mass-spectrometry- electron microscopy- cross-linking- co-immunoprecipitation- immunofluorescence- knock-out- phylogenetic profiles, gene fusion events...- ...
Protein Interaction Detection
Structural Characterization
- NMR (chemical shifts)- sequence conservation- binding essays- mutants & alanine-scanning
- X-ray- NMR- druggable pockets
P4
P3
P1A
P4A
P1
P2A
P6
P2
P8
P1B
P9 P10
P7P5
P9A P9B
P4
P3
P1A
P4A
P1
P2A
P6
P2
P8
P1B
P9 P10
P7P5
P9A P9B
Applications
- protein design- inhibitor discovery:
peptide mimickingligand dockingVLS
- association mechanism
Biophysical Analysis
Study of Protein-Protein Interactions
Structural Analysis at Atomic Resolution: Structural Analysis at Atomic Resolution: NMR and XNMR and X--rayray
Structural Analysis at Atomic Resolution: Structural Analysis at Atomic Resolution: NMR and XNMR and X--rayray
- Lo Conte, Chothia, Janin 1999 J.Mol.Biol. 285, 2177-2198- Chakrabarti, Janin 2002 Proteins 47, 334-343
Databases of ProteinDatabases of Protein--Protein ComplexesProtein Complexeshttp://pqs.ebi.ac.ukPQS
http://dockground.bioinformatics.ku.eduDOCKGROUND
• Introduction
•• Computational proteinComputational protein--protein dockingprotein docking• Geometric docking algorithms
• Docking by global energy optimization
• Comparison of docking methods
• Docking applications and future challenges
Motivation Motivation ……
- X-ray, NMR: Determination of complex structures remains difficult
ProteinProtein--Protein DockingProtein DockingGeneration of the structure of a protein-protein complex
from the individual protein structures
Motivation Motivation ……
- X-ray, NMR: Determination of complex structures remains difficult
ProteinProtein--Protein DockingProtein DockingGeneration of the structure of a protein-protein complex
from the individual protein structures
Motivation Motivation ……
- X-ray, NMR: Determination of complex structures remains difficult
- Low-resolution data on PPI available (cryo-EM, MS…)
ProteinProtein--Protein DockingProtein DockingGeneration of the structure of a protein-protein complex
from the individual protein structures
Motivation Motivation ……
- X-ray, NMR: Determination of complex structures remains difficult
- Low-resolution data on PPI available (cryo-EM, MS…)
- Understand energetics and mechanism of protein-protein association
ProteinProtein--Protein DockingProtein DockingGeneration of the structure of a protein-protein complex
from the individual protein structures
Motivation Motivation ……- X-ray, NMR: Determination of complex structures remains difficult
- Low-resolution data on PPI available (cryo-EM, MS…)
- Understand energetics and mechanism of protein-protein association
- Protein design (diagnostic, environment) and drug discovery
ProteinProtein--Protein DockingProtein DockingGeneration of the structure of a protein-protein complex
from the individual protein structures
c
0
PROTEINS FAR APARTE
CLOSE CONTACT
SOME CONTACTS
NEARBY
ROTATION
ΔG’ = elect + desolv
ΔG = elect.
ΔG’’ = HB + vdW
c
0
PROTEINS FAR APARTE
CLOSE CONTACT
SOME CONTACTS
NEARBY
ROTATION
ΔG’ = elect + desolv
ΔG = elect.
ΔG’’ = HB + vdW
1)
2)
• Introduction
• Computational protein-protein docking
•• Geometric docking algorithmsGeometric docking algorithms• Docking by global energy optimization
• Comparison of docking methods
• Docking applications and future challenges
Fourier TransformFourier Transform
Fourier transform equations: Correlation function:
“Correlation Theorem”:
C(f) = G(f) H(-f)
If h(t) is real then H(-f) = [H(f)]*
C(f) = G(f) [H(f)]*
c(t) =
F(k) = FT( f(x) )
f(x) = IFT( F(k) )
c(t) = IFT( FT( g(τ) ) [FT( h(τ) )]* )
It re-express a function in terms of sinusoidal basis functions
FFT (Fast Fourier Transform)FFT (Fast Fourier Transform)
Fourier transform timing: N2 (if N= 106 1MHz CPU time ~2 weeks)Fast Fourier transform: Nlog2N (if N= 106 1MHz CPU time ~ 30 sec)
http://www.fftw.org/
Algorithms for efficient calculation of FT and IFT
- Most common: Cooley-Tukey FFT (divide and conquer)- Other: Prime-factor, Bruun's, Rader's, Bluestein's
Protein Docking Using FFTProtein Docking Using FFT
R
L L
RR
LRotate
Fast Fourier Transform
Complex Conjugate
Discretize
Discretize
Fast FourierTransform
Surface Interior
Correlation function
Protein Docking Using FFTProtein Docking Using FFT
Surface InteriorY Translation
Cor
rela
tion
X Translation
IFFT
L
RIFFT
Comp. cost can decrease by >104 (from N6 to N3lnN3)
ZDOCK performanceZDOCK performanceA Novel Shape Complementarity Function
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 10 100 1000
Number of Predictions
Succ
ess
Rate
Grid-based shape complementarity (GSC)GSC+Desolvation+ElectrostaticsPairwise shape complementarity (PSC)PSC +Desolvation+Electrostatics
• Introduction
• Computational protein-protein docking
• Geometric docking algorithms
•• Docking by global energy optimizationDocking by global energy optimization• Comparison of docking methods
• Docking applications and future challenges
ProteinProtein--Protein Docking EnergyProtein Docking Energy
‘soft’ vdW =
(ECEPP/3)
= 0.03 kcal/mole * ASA(apolar)
E E = = EEvwvw + + EEelel + + EEhbhb + + EEhphp
Max = 20 kcal/moleMin = -20 kcal/mole
dqq
ij
jsiE 4
0.323 2el =
Eel
Eel
Calculate maps
Positioning (x 120)
RECEPTOR LIGAND
PREDICTED COMPLEX
Monte Carlo sampling(positional)
Local minimization
Metropoliscriteria
Solutionaccepted
YES
NOSolutionrejected
Conformational stack
Low energy solutionsRMSD > 4 Å
20000 energy evaluations
Monte Carlo sampling(ligand interface side-chains)
Local minimization
Solutionaccepted
NO Solutionrejected
1000 energy evaluationsper flexible torsion angle
Metropoliscriteria
YESRIGID BODY RIGID BODY
DOCKINGDOCKING
Lowest energy solution
(including solvation)
SIDESIDE--CHAIN CHAIN REFINEMENTREFINEMENT
ICM Protein-Protein Docking
FernFernáándezndez--Recio et al. 2002 Protein Recio et al. 2002 Protein SciSci. 11, 280. 11, 280--291291
EnergyEnergy = = vdwvdw + el + + el + hbhb + +
desolvdesolv
xx--ray complexray complexBest rigidBest rigid--body body docking solutiondocking solution
RigidRigid--Body Docking + SideBody Docking + Side--Chain RefinementChain Refinement
After refinementAfter refinement
• 35% rank 1
Fernandez-Recio et al. 2002 Prot. Sci. 11, 280-291
ICM dockingwww.molsoft.com
pyDock: scoring of rigidpyDock: scoring of rigid--body docking body docking orientations by electrostatics + desolvationorientations by electrostatics + desolvation
Max = +1 kcal/moleMin = -1 kcal/mole
dqq
ij
jsiE 4
0.323 2el =
Eel
Eel
E E = = EEelel + + EEsolvsolv
ASPs forinterface/water
ASPs fromoctanol/water
ASPs are optimized for protein dockingASPs are optimized for protein docking
FTDOCK’s docking sets:(80 unbound cases)
ZDOCK’s docking sets:(80 unbound cases)
pyDock
FTDOCK
(random)
pyDock
ZDOCK(random)
pyDock pyDock –– Cheng, Cheng, BlundellBlundell, , FernandezFernandez--Recio (2007) Recio (2007) ProteinsProteins 68, 50368, 503--515515
pyDock: scoring of rigidpyDock: scoring of rigid--body docking body docking orientations by electrostatics + desolvationorientations by electrostatics + desolvation
• Introduction
• Computational protein-protein docking
• Geometric docking algorithms
• Docking by global energy optimization
•• Comparison of docking methodsComparison of docking methods• Docking applications and future challenges
DOCKING VALIDATIONDOCKING VALIDATIONCAPRI: A Critical Assessment of CAPRI: A Critical Assessment of PRedictedPRedicted InteractionsInteractions
1st CAPRI – Sep02 La Londe (France)Special issue, in:PROTEINS: Structure, Function, and Genetics 52 (July 2003)
http://www.ebi.ac.uk/msd-srv/capri/
T01Hpr (unbound) HPr kinase (unbound) T02
VP6 (unbound)Fab (bound)
T03Hemagglutinin (unbound) Fab (bound)
T04, T05, T06α-amylase (unbound)VHH (bound)
T07TCRβ (unbound)speA (unbound)
2nd CAPRI – Dec04 Gaeta (Italy)Special issue, in:PROTEINS: Structure, Function, and Bioinformatics 60 (July 2005)
3rd CAPRI – Apr07 Toronto (Canada) Special issue, in:PROTEINS: Structure, Function, and Bioinformatics 69 (December 2007)
DOCKING VALIDATIONDOCKING VALIDATIONCAPRI: A Critical Assessment of CAPRI: A Critical Assessment of PRedictedPRedicted InteractionsInteractions
1st CAPRI 1st CAPRI -- PredictionsPredictions
Fernandez-Recio et al. (2003) Proteins 52, 113-117
6 groups:2 acceptable models
3 groups:1 acceptable models
5 groups:no acceptable models
…
Fernandez-Recio et al. (2005) Proteins 60, 308-313
T08 T10 T11 T12
T13 T14
7.67.6ÅÅ8.58.5ÅÅ
6.06.0ÅÅ 0.70.7ÅÅ
11.111.1ÅÅ
0.60.6ÅÅ
3.03.0ÅÅ
T184.14.1ÅÅ
T19
2nd CAPRI 2nd CAPRI -- PredictionsPredictions
22ndnd CAPRI CAPRI –– Target 14Target 14
Fernandez-Recio et al. (2005) Proteins 60, 308-313
Template: Template: protein protein phosphatasephosphatase 11αα
ModelledModelled Ligand: Ligand: protein protein phosphatasephosphatase 11ββ
ID ID 92.9%92.9%
Bound receptor: Bound receptor: MYPT1MYPT1
Fernandez-Recio et al. (2005) Proteins 60, 308-313
Template: Template: protein protein phosphatasephosphatase 11αα
ModelledModelled Ligand: Ligand: protein protein phosphatasephosphatase 11ββ
ID ID 92.9%92.9%
Bound receptor: Bound receptor: MYPT1MYPT1
DockingDocking
Rank 1Rank 1Ligand Ligand RMSD: RMSD:
0.60.6ÅÅ
22ndnd CAPRI CAPRI –– Target 14Target 14
Fernandez-Recio et al. (2005) Proteins 60, 308-313
Template: Template: protein protein phosphatasephosphatase 11αα
ModelledModelled Ligand: Ligand: protein protein phosphatasephosphatase 11ββ
ID ID 92.9%92.9%
Bound receptor: Bound receptor: MYPT1MYPT1
DockingDocking
Rank 1Rank 1Ligand Ligand RMSD: RMSD:
0.60.6ÅÅ
22ndnd CAPRI CAPRI –– Target 14Target 14
• Introduction
• Computational protein-protein docking
• Geometric docking algorithms
• Docking by global energy optimization
• Comparison of docking methods
•• Docking applications and future challengesDocking applications and future challenges
Federici et al. (2006) Trends Plant Sci 11, 65 Fort et al. (2007) JBC 282, 31444
Bonivento et al. (2007) Proteins 70, 294
Bavro et al. Mol Cell (in press)
Complex Structure Prediction by PyDock: ExamplesComplex Structure Prediction by PyDock: Examples
Medina et al. (2008) Proteins
FNR
/ FN
R /
ferr
edox
infe
rred
oxin
FNR
/ FN
R /
flavo
doxi
nfla
vodo
xin
Q
QH2
PSIcyt bf
PC +
2+PCPSII
H2O2 O2H+4 +
2+
Fd 3+
Fld
FdFld FNR
FNR NADP +
NADPH
Q
QH2
Q
QH2
PSIPSIcyt bfcyt bf
PC +
2+PC
PC +PC +
2+PC 2+PC 2+PCPSII
H2O2 O2H+4 +
PSIIPSII
H2O2 O2H+4 +H2O2H2O2 O2H+4 + O2O2H+4H+H+4 +
2+
Fd 3+
Fld
FdFld
2+
Fd 3+
Fld
FdFld FNR
FNR
FNRFNR
FNRFNR NADP +
NADPH
NADP +
NADPH
1mlc
2pcf
1ca0
∑=
⎟⎟⎠
⎞⎜⎜⎝
⎛ −100
11001
kUnbi
Bndik
Unbi
ASAASAASA
Averaged buried surfaceAveraged buried surface(ABS)(ABS)
ABSABSABSABS
NIP MAXi
i −−
=
Normalized ABS or Normalized ABS or Interface Propensity Interface Propensity
for residue i:for residue i:
Interface propensity map from docking landscape
FernandezFernandez--Recio et al. (2004) JMB 335, 843Recio et al. (2004) JMB 335, 843--865865
Binding site prediction from rigid-body docking
FernandezFernandez--Recio et al. (2004) JMB 335, 843Recio et al. (2004) JMB 335, 843--865865
pyDockRST: use of restraints to filter pyDockRST: use of restraints to filter docking solutionsdocking solutions
A B
Docking solution i
Restraintresidues
Restraintresidues
Satisfied restraints
Satisfied restraints
Pseudo-Energy = -100*(satisfied restraints / total restraint residues)
< 6 Å
< 6 Å
< 6 Å
Crescendo + pyDockRSTCrescendo + pyDockRST
CRESCENDO CRESCENDO ((ChelliahChelliah, Blundell, Lovell), Blundell, Lovell)
pyDockRSTpyDockRST
Chelliah et al. (2006) JMB 357, 1669-1682
Crescendo + pyDockRSTCrescendo + pyDockRST
Introduction of evolutionary restraints dramatically improves the docking results
Chelliah et al. (2006) JMB 357, 1669-1682
ProteinProtein--Protein Docking MechanismProtein Docking Mechanism
Blundell & Fernandez-Recio (2006) Nature 444, 279
Multi-protein docking
Docking 1:1 Tethered docking Tethered docking + restraints
Multi-proteindocking ??
Mare Nostrum Supercomputerwww.bsc.es
- 94.21 Teraflops- 10,240 CPUs- 20 TB main memory- 370 TB disk storage- world 26th, Europe 8th
(www.top500.org; Jun 2008)
Protein-Protein Interaction - General- Protein-Protein Recognition, C. Kleanthous ed., Oxford University Press- Conte et al. (1999) J. Mol. Biol 285, 2177-2198- Estructura de Proteínas, C. Gómez-Moreno & J. Sancho coord., Editorial Ariel
Docking Simulations- Katchalski-Katzir et al. (1992) PNAS 89, 2195-2199- Halperin et al. (2002) Proteins 47, 409-443- Smith & Sternberg (2002) COSB 12, 28-35- Ritchie (2008) Curr. Protein Pept. Sci. 9, 1-15
CAPRI- Proteins Special Issues (July 2003, July 2005, December 2007)
ReferencesReferences
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