A Definition of Interfaces for Protein Oligomers

ITR Meeting 2002

A Definition of Interfaces for Protein Oligomers

Andrew Ban

Biochemistry & Computer Science

Duke University

ITR Meeting 2002Yih-En Andrew Ban


Protein-Protein Complexes

Cell Signaling

Retrovirus Propogation Venom Neutralization

Oxygen Transport

Ribonuclease Regulation


Protein-Protein Complexes

Amino Acid Synthesis Assisted Protein FoldingNitrogen Metabolism

DNA Upkeep


Macromolecular Interaction Scenario

Separation

Diffusion

Function

Interaction


Methods of Attack

• Experimental Binding Assays Mutagenesis

• Computational Molecular Simulation Docking Interface

Characterization


Current Knowledge

• Basic statistics• Geometric

complementarity• Hot-spot theory• Electrostatic steering


Interface Characterization

• Current paradigm Two components “Coarse” definitions Reproducibility issues

• Characterization needs General definition of the

“Interface” Localization of important

regions


Intuition

• Best separation is a “medial surface” between proteins

• Interesting regions should be protected in some manner


Planar Case


R3 Case

1BRS


Delaunay Triangulation


Pockets

[EFL98]


Retraction


2-Manifold with Boundary


Further Retraction

• Extension of the “seal” intuition

• Dome structure Identification by topological

persistence pairing [ELZ99]

• Relative Persistence Compare sizes of mouth vs. sink Gives a hierarchy of interfaces

su

susf

),(


Level-of-Focus Hierarchy

725,690 394,490 70.183 32.475 10.207

1BRS Interface: Seal Threshold (infinity to –infinity)


Level-of-Focus Hierarchy

3.5121 1.8840 1.0287 .70203 -infinity

1BRS Interface: Seal Threshold (infinity to –infinity)


Persistent = Important?

1A22 Interface: Hot Spots


Future Work

• Geometric and topological measures

• Energy measures Critical points Simultaneous critical points

• Extension to volumes Skin surface


Energy Maps

1BRS Interface: Isolines of Power Distance


Summary

• Current Status Definition of a surface of interaction

between proteins Construction of a hierarchy of

interfaces Apparent localization of the important

regions in protein-protein interactions

• Uniqueness Bridges biology, geometry, and

topology


Goals

• Hot-spot Prediction• Theoretical Mutagenesis• Computational Kinetics• Interface Classification


Acknowledgements

• Duke Biochemistry Johannes Rudolph

• Duke Computer Science Herbert Edelsbrunner Pankaj Agarwal Sergei Bespamyatnikh (UT

Dallas) Alper Üngör Yusu Wang

A Definition of Interfaces for Protein Oligomers

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