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

ITR Meeting 2003b Yih-En Andrew Ban Problem Statement Why & how do proteins dock?

ITR Meeting 2003b Yih-En Andrew Ban Objectives Construct a representation:  Aids in biochemical analysis.  Supplants the need for experiment. Issues:  Time  Accuracy

ITR Meeting 2003b Yih-En Andrew Ban Typical Methods Empirical Force Field  Molecular dynamics  Monte Carlo simulation Simplification/Hierarchy  Substructure manipulation  Rotamer libraries

ITR Meeting 2003b Yih-En Andrew Ban Biophysical Models GeometryEnergy Biochemical Meaning

ITR Meeting 2003b Yih-En Andrew Ban Relevance Establish a readily useable biochemical result. Hot-spot prediction.

ITR Meeting 2003b Yih-En Andrew Ban Intuition Medial surface captures the essentials of the interaction. Regions of importance are protected in some way.

ITR Meeting 2003b Yih-En Andrew Ban Concepts Voronoi diagram Delaunay triangulation Alphashapes Topological Persistence

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-En Andrew Ban

ITR Meeting 2003b Yih-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 2003b Yih-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

ITR Meeting 2003b Yih-En Andrew Ban Interface Hierarchy

ITR Meeting 2003b Yih-En Andrew Ban Interface Hierarchy

ITR Meeting 2003b Yih-En Andrew Ban Nomenclature Gate = seal triangle Flood = set of triangles and tetrahedra that are deleted and retracted Trench = trivial collapse

ITR Meeting 2003b Yih-En Andrew Ban Seal Graph

ITR Meeting 2003b Yih-En Andrew Ban Seal Graph (Zoom)

ITR Meeting 2003b Yih-En Andrew Ban External

ITR Meeting 2003b Yih-En Andrew Ban Hot-Spot Function where R is a residue p 0.. p k are the polygons of R S is the interface surface

ITR Meeting 2003b Yih-En Andrew Ban Hot-Spot Function

ITR Meeting 2003b Yih-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 2003b Yih-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 2003b Yih-En Andrew Ban Results & Comparison Hot-Spots Correct Neutral Correct Interface Surface 70.4%70.6% K&B79%68%

ITR Meeting 2003b Yih-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 2003b Yih-En Andrew Ban Acknowledgements Herbert Edelsbrunner Johannes Rudolph