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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.

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information within the interface surface of a protein protein complex

Information Within the Interface Surface of a Protein-Protein Complex

Yih-En Andrew Ban

Duke University

Biochemistry & Computer Science

problem statement
Problem Statement
  • Why & how do proteins dock?
objectives
Objectives
  • Construct a representation:
    • Aids in biochemical analysis.
    • Supplants the need for experiment.
  • Issues:
    • Time
    • Accuracy
typical methods
Typical Methods
  • Empirical Force Field
    • Molecular dynamics
    • Monte Carlo simulation
  • Simplification/Hierarchy
    • Substructure manipulation
    • Rotamer libraries
biophysical models
Biophysical Models

Energy

Geometry

Biochemical Meaning

relevance
Relevance
  • Establish a readily useable biochemical result.
  • Hot-spot prediction.
intuition
Intuition
  • Medial surface captures the essentials of the interaction.
  • Regions of importance are protected in some way.
concepts
Concepts
  • Voronoi diagram
  • Delaunay triangulation
  • Alphashapes
  • Topological Persistence
in practice
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
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
Nomenclature
  • Gate = seal triangle
  • Flood = set of triangles and tetrahedra that are deleted and retracted
  • Trench = trivial collapse
hot spot function
Hot-Spot Function
  • where R is a residue
  • p0 .. pkare the polygons of R
  • S is the interface surface
prediction
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
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
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
Acknowledgements
  • Herbert Edelsbrunner
  • Johannes Rudolph
ad