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university-logo The State of Affairs in Protein Modeling Andrew Gillette Department of Mathematics, Institute of Computational Engineering and Sciences University of Texas at Austin, Austin, Texas 78712, USA http://www.math.utexas.edu/users/agillette Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences Universit The University of Texas at Austin Jan 30 2008 1 / 20

The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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Page 1: The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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The State of Affairs in Protein Modeling

Andrew Gillette

Department of Mathematics,Institute of Computational Engineering and Sciences

University of Texas at Austin, Austin, Texas 78712, USAhttp://www.math.utexas.edu/users/agillette

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 1 / 20

Page 2: The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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Intro and Disclaimer

These slides are based mainly on talks by Patrice Koehl (UC Davis)and Michael Levitt (Stanford) given at the IMA tutorial on theMathematics of Proteins in January 2008 at the University of

Minnesota. Images from those talks are credited.

http://www.ima.umn.edu/2007-2008/T1.10-11.08

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The Fundamental Relationship

image by Patrice Koehl

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 3 / 20

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Abstract Problem Statement

f g

SEQUENCE FUNCTIONSTRUCTURE

A

f(A)

B

g(B)

C

white region = all possible elements

light blue region = range of function over known elements

dark blue region = known elements (i.e. information stored in PDB)

Abstract Problem Statements:1 Expand light and dark blue regions to their maximal size.2 Create measures on Sequence and Structure space.3 Determine “formulae” for f and g.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 4 / 20

Page 5: The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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Abstract Problem Statement

f g

SEQUENCE FUNCTIONSTRUCTURE

A

f(A)

B

g(B)

C

white region = all possible elements

light blue region = range of function over known elements

dark blue region = known elements (i.e. information stored in PDB)

Abstract Problem Statements:1 Expand light and dark blue regions to their maximal size.2 Create measures on Sequence and Structure space.3 Determine “formulae” for f and g.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 4 / 20

Page 6: The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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Abstract Problem Statement

f g

SEQUENCE FUNCTIONSTRUCTURE

A

f(A)

B

g(B)

C

1 Expand light and dark blue regions to their maximal size.

Protein Data Bank (PDB) currently has ≈48,000 proteins stored.

Research in this area primarily belongs to biochemists.

Many subtleties exist, for example. . .

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 5 / 20

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A Structural Subtlety

The chirality of a protein is relevant to its presence in Structure space.

common very rare

image by Michael Levitt

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Abstract Problem Statement

f g

SEQUENCE FUNCTIONSTRUCTURE

A

f(A)

B

g(B)

C

2 Create measures on Sequence and Structure space.

A “good measure” on a space S is a function m : S × S → R≥0 such that theoutput is small if and only if the two inputs have similar essential properties.

On Sequence space: a combinatorial problem, similar to phylogenetics.

On Structure space: Knot theoretical approaches by Isabel Darcy (U. Iowa),Jennifer Mann (UT Math), and others. Differential Geometry approaches byKoehl and others.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 7 / 20

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CATH Structure Classification

image by Patrice Koehl

Class

Architecture

Topology(read: geometry)

Homology (biological)

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Abstract Problem Statement

f g

SEQUENCE FUNCTIONSTRUCTURE

A

f(A)

B

g(B)

C

3 Determine “formulae” for f and g.

The function f is not well-behaved: two proteins which are close in structuralmeasure may be distant in sequence measure.

A large body of work focuses on studying g, i.e. how structure dictates function.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 9 / 20

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From Structure to Function

A protein’s function is dependent upon the forces involved in formingand maintaining its structure. In order of decreasing importance, theseforces are:

1 Bonded interactions (chemistry)2 Non-bonded interactions (van Der Wal forces, electrostatics)3 Solvent and environmental forces (not negligible)

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An explicit approach?

Solvent molecules (usually water) surround the protein, movemuch more rapidly than the protein, and “outnumber” proteinatoms ≈ 100 to 1.Although some explicit models have been attempted for moleculardynamics (see work of Levitt), force calculations are simplified byan implicit model.

image by Patrice Koehl

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 11 / 20

Page 13: The State of Affairs in Protein Modeling - ccom.ucsd.educcom.ucsd.edu/~agillette/research/proteinMath.pdf · The State of Affairs in Protein Modeling Andrew Gillette Department of

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Potential of Mean Force

(slide by Patrice Koehl)

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Potential of Mean Force

(slide by Patrice Koehl)

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Potential of Mean Force

We calculate the Potential of Mean Force by the following:

WT (X ) = UP(X ) + Wsol(X )

UP(X ) accounts for the internal energy of protein

Wsol(X ) accounts implicitly and exactly for the effect of thesolvent on the protein

We estimate Wsol(X ) by an artificial thermodynamics path.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 14 / 20

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Solvation of Free Energy

image by Patrice Koehl

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Solvation of Free Energy

Wnp measures the purely physical effect of putting the protein in water.

This is a geometrical question and is tackled by members of our lab,as well as others.

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 16 / 20

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Solvation of Free Energy

W Vacch and W Sol

ch measure the electrostatic forces of the protein with orwithout the presence of water.

These forces are computed by means of the Poisson Boltzmannequation. Such computations rest upon some crucial assumptions.

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PB problems

Problems with the basic Poisson Boltzmann equation:

Dimensionless ions: Number of ions present depends upon thesize of ions in question.

Ion-ion interactions: Not accounted for.

Ion-solvent interactions: Not accounted for.

Non-uniform solvent concentration: Water forms a hydrationlayer around protein.

Polarizaion: Assumed to be a linear response to E with constantproportion.

An alternative approach is to assume a density of dipoles withconstant module ρ0 yielding the Generalized Poisson-BoltmannLangevin Equation, however, . . .

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 18 / 20

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Generalized PB Langevin Equation

(slide by Patrice Koehl)

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 19 / 20

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References

PATRICE KOEHL http://nook.cs.ucdavis.edu/ koehl/

MICHAEL LEVITT http://csb.stanford.edu/levitt/

IMA TUTORIAL http://www.ima.umn.edu/2007-2008/T1.10-11.08

For a copy of these slides, please visit

http://www.math.utexas.edu/users/agillette/

Computational Visualization Center , I C E S (Department of Mathematics, Institute of Computational Engineering and Sciences UniversityThe University of Texas at Austin Jan 30 2008 20 / 20