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Information Within the Interface Surface of a Protein-Protein Complex Yih-En Andrew Ban Duke University Biochemistry & Computer Science
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 Energy Geometry 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
Nomenclature • Gate = seal triangle • Flood = set of triangles and tetrahedra that are deleted and retracted • Trench = trivial collapse
Hot-Spot Function • where R is a residue • p0 .. pkare the polygons of R • S is the interface surface
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
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