ProteinShop: A Tool for Protein Structure Prediction and Modeling

8/14/2019 ProteinShop: A Tool for Protein Structure Prediction and Modeling

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ProteinShop: A Tool for Protein

Structure Prediction andModeling

Silvia Crivelli

Computational Research Division

Lawrence Berkeley National Laboratory



The Protein Structure Prediction

ProblemTo determine how proteins, the building

blocks of living cells, fold themselves into

three-dimensional shapes that define the

role they play in life.



Importance of Protein Structure

Prediction• The shape of a protein determines its function.

• Knowledge of structure is used in many ways:

– Drug design – Design of synthetic proteins

– Re-engineering defective proteins

• Genome projects are providing sequences for many proteins whose structure will need to bedetermined.



Protein Structures

ProGly Leu Ser

Proteins consist of a long chain of

amino acids, the primary structure

N

O H

R H

N

O H

R H

N

O H

R H

N

O H

R H

N

OH

R H

N

OH

R H

N

OH

R H

N

OH

R H

Side chain

H-bond

Backbone

Amino acid



Protein Structures

ProGly Leu Ser

Proteins consist of a long chain of

amino acids, the primary structure

The constituent amino acids may

encourage hydrogen bonding thatform regular structures, called

secondary structures

The secondary structures fold

together to form a compact

3-dimensional shape, called

the tertiary structure

α -helix β -sheet



The problem can be formulated as a global

minimization problem, as it is assumed that thetertiary structure occurs at the global minimum of

the free energy function of the primary sequence

Ab Initio Approach

Our Goal: To provide an approach that relies more on physical

principles than on information from known proteins



Ab Initio MethodTertiary structure is

believed to minimize potential energy:

Min V MM

( x )

where x = atom coordinates

Difficulties: Proposed energy function may not

match nature

O(en2) local minima

Very large parameter space

e.g., modestly sized protein100 amino acids

~ 1,600 atoms

~ 4,800 variables





Secondary Structure Predictions

in Phase 1

SKIGIDGFGRIGRLVLRAALSCGAQ

SKIGIDGFGRIGRLVLRAALSCGAQ

CBBBB BCCCAAAAAAACCCBBBBBC

1135522356789992888566733

Sequence:

Type:

Weight:

Sequence:

Servers predict secondary

structure likely to be in a

target protein based on alarge database of known

proteins.



Matching the predicted strands is a

combinatorial problem

Which strands are paired?

Which orientation?

? ??

parallel anti-parallel

Which residues are paired?

odd even



There are n!2 n-2 possible

n-stranded motifs

96 motifs for n=4

960 motifs for n=5

It takes weeks tocreate some of theseconfigurations usingconstrained local

minimizations!

Distribution of Beta Sheets in Proteins with Applications to Structure Prediction

Ruckzinski, Kooperberg, Bonneau, and Baker, Proteins 48,2002



CASP4 Competition

• Fourth community-wide experiment on the

Critical Assessment of Techniques for Protein

Structure Prediction (2000)

• Our group predicted 8 proteins

•Largest protein had 240 aa•Most complex fold had 2 β-strands



ProteinShop

• Interactive tool for protein manipulation

• Designed to quickly create initial configurations

• It takes weeks to create a number of configurations

using constrained minimizations

• It takes a few hours to create the same

configurations with ProteinShop



Phase 1 with ProteinShop

Phase 1

Amino Acid Sequence

Phase 2

Initial Configurations

Final Configuration

2nd ary Structure

Prediction

Geometry

Generation

Structure Sequence

Direct

Manipulation

Pre-configuration


ProteinShop

takes minutes













CASP4 Competition (before ProteinShop)

CASP5 Competition (with ProteinShop)

•Our group predicted 20 proteins

•Largest protein had 417 aa

•Most complex fold had 13 β-strands

•Our group predicted 8 proteins

•Largest protein had 240 aa

•Most complex fold had 2 β-strands



Phase 2

Phase 1

Amino Acid Sequence

Phase2: Global

Optimization


Final Configuration

Subspace

Selection


Subspace

Optimization

Candidate

Selection

Final Configuration

Takes months toconverge usinghundreds of processors onSeaborg!



Phase 2 with ProteinShop

Phase 1

Amino Acid Sequence

Phase2: Global

Optimization


Final Configuration

Subspace

Selection


Subspace

Optimization

Candidate

Selection

Final Configuration

Monitoring

System

Direct

Manipulation

Steering

System

Will reducecomputation time



Monitoring System

• Monitor progress of overall optimization/eachoptimization process



Monitoring System

• Monitor progress of overall optimization/each

optimization process

• Alert user to important events during optimization

• A sudden drop in internal energy

• A group of processes getting stuck

• Test new heuristics for expanding nodes of the

tree



Steering System

• Change configurations during optimization toaccount for developments not anticipated during

Phase 1

• Manipulate proteins that don’t seem to be realistic

or that are stuck in a local minimum

• Allow pruning of the optimization tree•Assign multiple processes to a configuration that just had

a drop in internal energy

•Assign stuck processes to other configurations



Plans for the Future

Use of the monitoring and steering

features to develop and test a new

method for protein structure prediction

Compete in CASP6 (Critical Assessment

of Techniques for Protein Structure Prediction)

Expand and enhance ProteinShop



O. Kreylos, N. Max, B. Hamann,

S. Crivelli, and W. Bethel.

Interactive Protein Manipulation,

Winner of the Best ApplicationAward IEEE Visualization 2003,

Seattle.

ProteinShop

Available to academic and non-profit organizations

proteinshop.lbl.gov

Documents

ProteinShop: A Tool for Protein Structure Prediction and Modeling