3i - Zlab

abalonestrawΒιοτεχνολογία

2 Οκτ 2013 (πριν από 4 χρόνια και 10 μέρες)

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Protein Docking

Rong Chen

Boston University

BU Bioinformatics

The Lowest Binding Free
Energy
D
G

water

R

L

R

L

L

R

L

R

L

R

BU Bioinformatics

Protein Docking Using FFT

R

L

L

R

R

L

Rotate

Fast Fourier
Transform

Complex

Conjugate

Discretize

Discretize

Fast Fourier

Transform

Surface

Interior

Correlation function

BU Bioinformatics

Rotational Sampling


Evenly distributed Euler angles




Sampling Interval

Number of angles

20
°

1,800

15
°

3,600

12
°

9,000

10
°

14,400

8
°

27,000

6
°

54,000

4
°

180,000

BU Bioinformatics

Performance Evaluation


Success Rate
: given the number of
predictions(N
p
), 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 N
p.


BU Bioinformatics

Rotational Sampling Density

BU Bioinformatics

Rotational Sampling Density

BU Bioinformatics

Protein Docking Using FFT

R

L

L

R

R

L

Rotate

Fast Fourier
Transform

Complex

Conjugate

Discretize

Discretize

Fast Fourier

Transform

Surface

Interior

Correlation function

BU Bioinformatics

Protein Docking Using FFT

Surface

Interior

Binding Site

Y Translation

Correlation

X Translation

IFFT

Increase the speed by 10
7

L

R

BU Bioinformatics

An Effective Binding Free
Energy Function

van der Waals energy; Shape complementarity

Desolvation energy; Hydrophobicity

Electrostatic interaction energy

Translational, rotational and vibrational free energy changes

Number of atom pairs of type
i

Desolvation energy for an atom pair of type
i

BU Bioinformatics

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

9
i

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

9
i

1

1

9
i

9
i

1

1

1

1

9
i

1

R
GSC

L
GSC

Grid
-
based

Shape Complementarity

BU Bioinformatics

R
PSC

L
PSC

1+3
i

1+3
i

1+3
i

1+9
i

1+3
i

1+3
i

1+9
i

1+9
i

1+3
i

1+3
i

1+3
i

1+3
i

1+9
i

1+3
i

3
i

3
i

3
i

3
i

3
i

3
i

9
i

3
i

3
i

3
i

3
i

9
i

3
i

3
i

9
i

3
i

3
i

9
i

3
i

3
i

3
i

3
i

3
i

3
i

3
i

3
i

2

2

3

3

2

3

2

2

3

5

2

3

5

2

3

2

3

2

2

3

3

2

3

2

1

1

1

1

1

1

Pairwise

Shape Complementarity

BU Bioinformatics

PSC vs. GSC on Success Rate

BU Bioinformatics

PSC vs. GSC on Hit Count

BU Bioinformatics

Why PSC works better than GSC?

BU Bioinformatics

A

B

C

D

Why PSC works better than GSC?

BU Bioinformatics

A Receptor
-
Ligand Complex

BU Bioinformatics

An Effective Binding Free
Energy Function

van der Waals energy; Shape complementarity

Desolvation energy; Hydrophobicity

Electrostatic interaction energy

Translational, rotational and vibrational free energy changes

Number of atom pairs of type
i
-
j

Desolvation energy for an atom pair of type
i
-
j

BU Bioinformatics

Impact of Desolvation and
Electrostatics

BU Bioinformatics

Impact of Desolvation and
Electrostatics

BU Bioinformatics

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)



BU Bioinformatics

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



BU Bioinformatics

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/

BU Bioinformatics

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




BU Bioinformatics

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/f
rames.htm



BU Bioinformatics

HEX


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


spherical polar Fourier correlations


http://www.biochem.abdn.ac.uk/hex/

BU Bioinformatics

Approach Overview

PDB1

PDB2

PDB Processing

ZDOCK: Initial
-
stage Docking

RDOCK: Refinement
-
stage Docking

Clustering

Final 10 predictions

Biological information

BU Bioinformatics

Example:


CAPRI Target 6:
α
-
amylase / Camelid
VHH domain