Computational Approaches to Studies of Protein-Protein Interactions*

10/5/98


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Table of Contents

Computational Approaches to Studies of Protein-Protein Interactions*

The players:

Topics of this seminar

What draws two proteins together?

The reach of electrostatic attraction/repulsion...

In early work* we used similar potentials to guide manual docking.

Manual docking...

Manual docking...

Structures like this can be refined...

Manual docking leaves a lot to be desired...

Brownian Dynamics can simulate the combined effect of intermolecular forces and random, Brownian motion

Brownian dynamics...

Brownian Dynamics calculations for cytochrome c3 and flavodoxin show how the electrostatic potential field favors certain “contacts”

Caveat: Productive complex may not be stable.

What holds interacting proteins together?

Statistical analysis of protein-protein interfaces*

Patch analysis by Jones & Thornton*...

Is a geometric match likely to work?

Lock & Key versus Induced Fit...

The limits of these values...

The Barstar comparison is a bit more than might be expected, but...

Some more perspective: Different experimental structures vary considerably*

Using a geometric filter to select structures for further analysis

The problem is that its is a massive calculation and it needs to have “soft” character.

Two general approaches tried...

Ludi and Nuno’s approach*...

BoGIE...

BoGIE...

Location of closest docked structure in the 1000 best geometric fits:

Comparing the #1 cluster to the X-ray structure of the complex

Obviously, the geometric filter works in most cases.

Applying an interaction score to structures from a geometric filter

P(2),Coulombic Electrostatic Interactions

P(3), “Solvent” Exclusion*

P(4), Pairwise amino acid contacts

Training the Scoring function:

Table of final results with Global Scoring:

Summary of method

Some predictions using these methods

The best fit binding model...

Docking using the BiGGER algorithm suggests the location of the two sites.

The two sites on flavodoxin and the single high scoring site on cytochrome c3...

Author: John E. Wampler

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