Information within the interface surface of a protein protein complex
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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

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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


Interface hierarchy

Interface Hierarchy


Interface hierarchy1

Interface Hierarchy


Nomenclature

Nomenclature

  • Gate = seal triangle

  • Flood = set of triangles and tetrahedra that are deleted and retracted

  • Trench = trivial collapse


Seal graph

Seal Graph


Seal graph zoom

Seal Graph (Zoom)


External

External


Hot spot function

Hot-Spot Function

  • where R is a residue

  • p0 .. pkare the polygons of R

  • S is the interface surface


Hot spot function1

Hot-Spot Function


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


Results comparison

Results & Comparison


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


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