Information Within the Interface Surface of a Protein-Protein Complex

1. Information Within the Interface Surface of a Protein-Protein Complex Yih-En Andrew Ban Duke University Biochemistry & Computer Science

2. Problem Statement • Why & how do proteins dock?

3. Objectives • Construct a representation: • Aids in biochemical analysis. • Supplants the need for experiment. • Issues: • Time • Accuracy

4. Typical Methods • Empirical Force Field • Molecular dynamics • Monte Carlo simulation • Simplification/Hierarchy • Substructure manipulation • Rotamer libraries

5. Biophysical Models Energy Geometry Biochemical Meaning

6. Relevance • Establish a readily useable biochemical result. • Hot-spot prediction.

7. Intuition • Medial surface captures the essentials of the interaction. • Regions of importance are protected in some way.

8. Concepts • Voronoi diagram • Delaunay triangulation • Alphashapes • Topological Persistence

19. 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

20. 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

21. Interface Hierarchy

22. Interface Hierarchy

23. Nomenclature • Gate = seal triangle • Flood = set of triangles and tetrahedra that are deleted and retracted • Trench = trivial collapse

24. Seal Graph

25. Seal Graph (Zoom)

26. External

27. Hot-Spot Function • where R is a residue • p0 .. pkare the polygons of R • S is the interface surface

28. Hot-Spot Function

29. 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

30. 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

31. Results & Comparison

32. 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…

33. Acknowledgements • Herbert Edelsbrunner • Johannes Rudolph