information within the interface surface of a protein-protein complex yih-en andrew ban duke...

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?


Objectives

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

• Issues: Time Accuracy


Typical Methods

• Empirical Force Field Molecular dynamics Monte Carlo simulation

• Simplification/Hierarchy Substructure manipulation Rotamer libraries


Biophysical Models

GeometryEnergy

Biochemical Meaning


Relevance

• Establish a readily useable biochemical result.

• Hot-spot prediction.


Intuition

• Medial surface captures the essentials of the interaction.

• Regions of importance are protected in some way.


Concepts

• Voronoi diagram

• Delaunay triangulation

• Alphashapes

• Topological Persistence


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


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

),(


Interface Hierarchy


Nomenclature

• Gate = seal triangle

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

• Trench = trivial collapse


Seal Graph


Seal Graph (Zoom)


External


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()(


Hot-Spot Function

k

i t

ti S

RpRh

0 )(area

)(area)area()(


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


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


Results & Comparison

Hot-Spots Correct

Neutral Correct

Interface Surface

70.4% 70.6%

K&B 79% 68%


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…


Acknowledgements

• Herbert Edelsbrunner

• Johannes Rudolph

information within the interface surface of a protein-protein complex yih-en andrew ban duke...

Documents