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