coarse and reliable geometric alignment for protein docking yusu wang stanford university joint work...

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Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J. Rudolph Duke University

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Challenges Physical and biochemical mechanism Binding sites? Energy function: hydrophobicity, electrostatics, etc High complexity Thousands of atoms High dimension, flexibility

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Page 1: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Coarse and Reliable Geometric Alignment

for Protein Docking

Yusu WangStanford University

Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J. Rudolph

Duke University

Page 2: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Motivation

How proteins interact with each other?

Docking problem Predict docking configuration

Page 3: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Challenges

Physical and biochemical mechanism Binding sites? Energy function: hydrophobicity, electrostatics, etc

High complexity Thousands of atoms High dimension, flexibility

Page 4: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Coarse alignment Rigid molecules Small sets of candidates

Refinement Flexibility, chemical information

Two-step Approach

Page 5: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Coarse Alignment

Goal

A relatively small set of possible configurations

Page 6: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

not too tight, global fitting …

Lock and Key Principle

… To use an image, I would say that enzyme and glycoside have to fit into each other like a lock and a key, in order to exert a

chemical effect on each other…

--- Emil Fischer, 1894

QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.

Geometric complementary at a coarse level

Page 7: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Coarse Alignment Algorithm

Capture features (protrusions, cavities)

Align these features

Page 8: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Capture Features

Previous work: feature points Connolly function

[Connolly, 83]

Our work: feature pairs Describe more global features Specify importance

Page 9: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Capture Feature Pairs

Height function as example

Extend to all directions -- Elevation function

Page 10: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

k-legged Maxima of Elevation

1-legged 2-legged 3-legged 4-legged

[Agarwal, Edelsbrunner, Harer, Wang, SOCG’04]

Page 11: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Examples

2-legged 4-legged3-legged

Page 12: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

3-Legged Maximum

Page 13: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

In Short :

Each maximum captures a feature on surface

Four types of features

Collect feature pairs: Any two points within the same maximum

A concise representation of meaningful features!

Page 14: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Surface Representation using Elevation

Page 15: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Coarse Alignment Algorithm

Describe protrusions and cavities (via feature pairs)

Align features

Page 16: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

PairMatch Alg:

Take a feature pair from each set Align two feature pairs, get T Rank T ’s by their scores

Output ranked sequence of configurations

Align Features

Page 17: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Reassembly of Known Complexes

A test set of 25 protein complexes CoarseAlign: take top 100 ranked coarse alignments Refinement: using local improvement (Choi et al.)

Page 18: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Docking Results (CoarseAlign)

pdb-id Rank RMSD (Å)1BRS 1 1.591A22 2 2.752PTC 1 4.551MEE 1 1.331CHO 1 2.711JLT 8 3.641CSE 2 2.213SGB 1 3.213HLA 1 1.87

Page 19: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Docking Results (Refinement)

pdb-id Rank.refine RMSD.refine1BRS 1 0.541A22 1 1.082PTC 1 0.661MEE 1 0.571CHO 1 0.991JLT 1 1.571CSE 1 0.823SGB 1 2.243HLA 1 0.78

Page 20: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Overall

23/25 return a near-native configuration w/o false positives

Page 21: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Unbound Protein Docking

Docking benchmark by [Chen et al.’03] Take 49 out of 59 complexes

Page 22: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Sample ResultsTop 2,000 All outputs

pdb-id RMSD(Å) Hits RMSD (Å) Size1ACB 3.70 20 1.75 14,4261AVW 5.51 8 5.42 23,5651BRC 4.66 35 4.66 12,7701BRS 1.60 7 1.60 11,6071CGI 3.04 5 3.04 10,1351CHO 2.35 27 2.35 11,8151CSE 3.15 7 2.74 21,0681DFJ 6.44 2 6.44 35,231

1MAH 2.78 4 2.78 25,402

Page 23: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

More Results

Output size: All < ~50,000, most < 25,000

Quality Among top 2,000 ranked configurations

38/49 produce at least one with < 6Å Among all outputs

47/49 produce at least one with < 6Å

Page 24: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Summary

Elevation function -> meaningful features Useful coarse alignments

Combine with refinement for the unbound case

Page 25: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Sample proteins

1A22 1JLT 3HLA

Page 26: Coarse and Reliable Geometric Alignment for Protein Docking Yusu Wang Stanford University Joint Work with P. K. Agarwal, P. Brown, H. Edelsbrunner, J

Related Docking Packages

FTDock, DOT, ZDock: FFT-based Shape complementary, electrostatics

HEX: Fourier correlation GRAMM: FFT (focus on low resolution docking) BiGGER PPD: Geometric Hashing