Information Within the Interface Surface of a

Protein-Protein Complex

Yih-En Andrew Ban

Duke University

Biochemistry & Computer Science

ITR Meeting 2003bYih-En Andrew Ban

Problem Statement

• Why & how do proteins dock?

ITR Meeting 2003bYih-En Andrew Ban

Objectives

• Construct a representation: Aids in biochemical analysis. Supplants the need for experiment.

• Issues: Time Accuracy

ITR Meeting 2003bYih-En Andrew Ban

Typical Methods

• Empirical Force Field Molecular dynamics Monte Carlo simulation

• Simplification/Hierarchy Substructure manipulation Rotamer libraries

ITR Meeting 2003bYih-En Andrew Ban

Biophysical Models

GeometryEnergy

Biochemical Meaning

ITR Meeting 2003bYih-En Andrew Ban

Relevance

• Establish a readily useable biochemical result.

• Hot-spot prediction.

ITR Meeting 2003bYih-En Andrew Ban

Intuition

• Medial surface captures the essentials of the interaction.

• Regions of importance are protected in some way.

ITR Meeting 2003bYih-En Andrew Ban

Concepts

• Voronoi diagram

• Delaunay triangulation

• Alphashapes

• Topological Persistence

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

ITR Meeting 2003bYih-En Andrew Ban

In Practice

• Construct Delaunay triangulation

• Construct Alphashape filtration Orders simplices based upon size

• Apply pairing algorithm on the Alphashape filtration Identification of protected regions

• Construct retraction hierarchy Removal of initial unprotected region Removal of protected regions

• Construction of interfaces

ITR Meeting 2003bYih-En Andrew Ban

Seal Function

• where s is the size of the orthogonal ball of the triangle

• where u is the size of the orthogonal ball of the tetrahedra

su

susf

),(

ITR Meeting 2003bYih-En Andrew Ban

Interface Hierarchy

ITR Meeting 2003bYih-En Andrew Ban

Interface Hierarchy

ITR Meeting 2003bYih-En Andrew Ban

Nomenclature

• Gate = seal triangle

• Flood = set of triangles and tetrahedra that are deleted and retracted

• Trench = trivial collapse

ITR Meeting 2003bYih-En Andrew Ban

Seal Graph

ITR Meeting 2003bYih-En Andrew Ban

Seal Graph (Zoom)

ITR Meeting 2003bYih-En Andrew Ban

External

ITR Meeting 2003bYih-En Andrew Ban

Hot-Spot Function

• where R is a residue

• p0 .. pk are the polygons of R

• S is the interface surface

k

i t

ti S

RpRh

0 )(area

)(area)area()(

ITR Meeting 2003bYih-En Andrew Ban

Hot-Spot Function

k

i t

ti S

RpRh

0 )(area

)(area)area()(

ITR Meeting 2003bYih-En Andrew Ban

Prediction

• Kortemme & Baker (2002) 19 protein-protein complexes 234 residues 71 hot, 163 neutral

• Interface surface generation Heavy atoms only

• h(R) theshold = 3.75

• ddG threshold = 2.0 kcal/mol

ITR Meeting 2003bYih-En Andrew Ban

Competing Method

• Kortemme & Baker (2002) virtual alanine scanning simple force-field model rotamer library Monte Carlo Optimization full atomic detail

• ddG threshold = 1.0 kcal/mol

ITR Meeting 2003bYih-En Andrew Ban

Results & Comparison

Hot-Spots Correct

Neutral Correct

Interface Surface

70.4% 70.6%

K&B 79% 68%

ITR Meeting 2003bYih-En Andrew Ban

Conclusion

• Interface surface Biochemically relevant Reasonable model for analyzing protein-

protein interactions Information encoded within the interface is

substantial – hot spots can be predicted!?

• Further work Refinement of h(R) Investigation into protected regions Visualization etc…

ITR Meeting 2003bYih-En Andrew Ban

Acknowledgements

• Herbert Edelsbrunner

• Johannes Rudolph