protein docking

Protein Docking

Rong ChenBoston University

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The Lowest Binding Free Energy G

water

RL

RL

LR

L

R

LR

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Protein Docking Using FFT

R

L L

RR

LRotate

Fast Fourier Transform

Complex Conjugate

Discretize

Discretize

Fast FourierTransform

Surface Interior

Correlation function

21 11( , ) ( , ) ( , ) IFT{IFT[ ( , )] DFT[ ( , )]}

l

N N

mScore o p R l m L l o m p R l m L l o m p

N

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Rotational Sampling

• Evenly distributed Euler angles

Sampling Interval Number of angles20° 1,80015° 3,60012° 9,00010° 14,4008° 27,0006° 54,0004° 180,000

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Performance Evaluation

• Success Rate: given the number of predictions(Np), success rate is the percentage of complexes in the benchmark for which at least one hit has been obtained.

• Hit Count: the average number of hits over all complexes at a particular Np.

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Rotational Sampling Density

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

6 8 10 12 14 16 18 20Rotational Sampling Interval

Succ

ess

Rat

e

Np=1000 Np=500 Np=200Np=100 Np=50 Np=20Np=10

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Rotational Sampling Density

0

5

10

15

20

0 100 200 300 400 500 600 700 800 900 1000

Number of Predictions

Hit

Cou

nt

6°

20°

15°

12°

10°

8°

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Protein Docking Using FFT

R

L L

RR

LRotate

Fast Fourier Transform

Complex Conjugate

Discretize

Discretize

Fast FourierTransform

Surface Interior

Correlation function

21 11( , ) ( , ) ( , ) IFT{IFT[ ( , )] DFT[ ( , )]}

l

N N

mScore o p R l m L l o m p R l m L l o m p

N

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Protein Docking Using FFT

Surface Interior Binding SiteY Translation

Cor

rela

tion

X Translation

IFFT

Increase the speed by 107

L

R

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An Effective Binding Free Energy Function

vdW desol elec const

vdW

desol

elec

const

ΔG=ΔE +ΔG +ΔE +ΔG

ΔE :

ΔG :

ΔE :

ΔG :

van der Waals energy; Shape complementarityDesolvation energy; HydrophobicityElectrostatic interaction energyTranslational, rotational and vibrational free energy changes

desolΔG = N ΔG

N :

ΔG :

i ii

i

i

Number of atom pairs of type iDesolvation energy for an atom pair of type i

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9i 9i 9i 9i 9i

9i 9i 9i 9i 9i

9i 9i 9i

9i 9i 9i

9i 9i 9i 9i 9i

9i 9i 9i 9i 9i 11

1 11 1 1

11

1 11

1 11

11

11

1 11 1 1

1

1 1 9i

1 1 9i 9i 1

1 1

1

9i 1

RGSC LGSC

Grid-based Shape Complementarity

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RPSC LPSC

1+3i

1+3i 1+3i 1+9i

1+3i 1+3i 1+9i 1+9i 1+3i

1+3i 1+3i

1+3i

1+9i 1+3i

3i 3i 3i 3i 3i

3i 9i 3i 3i 3i

3i 9i 3i

3i 9i 3i

3i 9i 3i 3i 3i

3i 3i 3i 3i 3i 22

3 32 3 2

23

5 23

5 23

23

22

3 32 3 2 1

1

1

11

1

PairwiseShape Complementarity

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PSC vs. GSC on Success Rate

PSC vs. GSC for Unbound Docking

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 10 100 1000

Number of Predictions

Succ

ess

Rat

e

PSC

GSC

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PSC vs. GSC on Hit CountPSC vs. GSC for Unbound Docking

0

1

2

3

4

5

6

0 100 200 300 400 500 600 700 800 900 1000

Number of predictions

Hit

Cou

nt

PSC

GSC

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Why PSC works better than GSC?

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A

B

C

D

Why PSC works better than GSC?

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A Receptor-Ligand ComplexA Receptor-Ligand Complex

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An Effective Binding Free Energy Function

vdW desol elec const

vdW

desol

elec

const

ΔG=ΔE +ΔG +ΔE +ΔG

ΔE :

ΔG :

ΔE :

ΔG :

van der Waals energy; Shape complementarityDesolvation energy; HydrophobicityElectrostatic interaction energyTranslational, rotational and vibrational free energy changes

desolj

ΔG = N ΔG

N :

ΔG :

ij iji

ij

ij

Number of atom pairs of type i-jDesolvation energy for an atom pair of type i-j

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Impact of Desolvation and Electrostatics

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 10 100 1000Number of Predictions

Succ

ess

Rat

e

PSCPSC+DesolvationPSC + Desolvation + Electrostatics

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Impact of Desolvation and Electrostatics

0

1

2

3

4

5

6

7

8

0 100 200 300 400 500 600 700 800 900 1000Number of Predictions

Hit

Cou

nt

PSCPSC+DEPSC + Desolvation + Electrostatics

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Other available Docking Software

• Fast Fourier Transform or FFT (Katchalski-Katzir, Sternberg, Vakser, Ten Eyck groups)

• Computer vision based method (Nussinov group, 1999)

• Boolean operations (Palma et al., 2000)• Polar Fourier correlations (Ritchie & Kemp,

2000)• Genetic algorithm (Gardiner, Burnett groups)• Flexible docking (Abagyan, 2002)

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3D-Dock

• Michael J.E. Sternberg, Imperial Cancer Research Fund, London, UK.

• FTDock: Grid-based shape complementarity, FFT.

• RPScore: empirical pair potential.• MultiDock: refinement.• http://www.bmm.icnet.uk/docking/index.html

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GRAMM

• Ilya A. Vakser, State University of New York at Stony Brook.

• Geometric fit and hydrophobicity• FFT• Low resolution docking• http://reco3.ams.sunysb.edu/gramm/

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DOT

• Lynn F. Ten Eyck, University of California, San Diego.

• Grid-based shape complemetarity, elctrostatics• FFT• http://www.sdsc.edu/CCMS/Papers/

DOT_sc95.html

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ICM

• Ruben Abagyan, The Scripps Research Institute, La Jolla.

• Pseudo-Brownian rigid-body docking• Biased Probability Monte Carlo

Minimization of the ligand interacting side-chains.

• http://abagyan.scripps.edu/lab/web/man/frames.htm

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HEX

• Dave Ritchie, University of Aberdeen, Aberdeen, Scotland, UK

• spherical polar Fourier correlations • http://www.biochem.abdn.ac.uk/hex/

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Approach Overview

PDB1 PDB2

PDB Processing

ZDOCK: Initial-stage Docking

RDOCK: Refinement-stage Docking

Clustering

Final 10 predictions

Bio

logi

cal i

nfor

mat

ion

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Example:

• CAPRI Target 6: α-amylase / Camelid VHH domain