Protein Folding Programs

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Protein Folding Programs

• By
• Asim OKUR
• CSE 549
• November 14, 2002

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Protein Structure

• DNA Sequence ? Protein Sequence ? Structure ?
  (Mis)function
• It is believed that all the information necessary
  to determine the structure of a protein is
  present in its primary sequence.

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Protein Folding Programs

• Protein folding is one of the biggest
  computational challenges
• Different types of folding and structure
  predictions programs
• Simulations
• Homology Modeling Approaches

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Simulations

• Simulate the real behavior of proteins
• High detail, short time scales
• 2 main simulation types
• Molecular Dynamics
• Monte Carlo

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The Energy Function

• Calculate energies for each particle
• Since long range interactions important for each
  pair of particles the pair-wise interactions
  should be calculated

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Homology Modeling

• Template Selection and Fold Assignment
• Target Template Alignment
• Model Building
• Loop Modeling
• Sidechain Modeling
• Model Evaluation

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Fold Assignment and Template Selection

• Identify all protein structures with sequences
  related to the target, then select templates
• 3 main classes of comparison methods
• Compare the target sequence with each database
  sequence independently, pair-wise sequence
  sequence comparison, BLAST and FASTA
• Multiple sequence comparisons to improve
  sensitivity, PSI-BLAST
• Threading or 3-D template matching methods

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Target Template Alignment

• Most important step in Homology Modeling
• A specialized method should be used for alignment
• Over 40 identity the alignment is likely to be
  correct.
• Regions of low local sequence similarity become
  common when overall sequence identity is under
  40. (Saqi et al., Protein Eng. 1999)
• The alignment becomes difficult below 30
  sequence identity. (Rost, Protein Eng. 1999)

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Model Building

• Construct a 3-D model of the target sequence
  based on its alignment on template structures
• Three different model building approaches
• Modeling by rigid body assembly
• Modeling by segment matching
• Modeling by satisfaction of spatial restraints
• Accuracies of these models are similar
• Template selection and alignment have larger
  impact on the model

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• Screenshots from the Homology Modeling Server
  Swiss-Model
• Construct a framework using known protein
  structures
• Generate the location of the target amino acids
  on the framework
• If loop regions not determined, additional
  database search or short simulations

Swiss-MOD Web Server
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• Procedure of the MODELLER program
• After obtaining restraints run a geometry
  optimization or real-space optimization to
  satisfy them

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Errors in Homology Models

• Errors in sidechain packing
• Distortions and shifts in correctly aligned
  regions
• Errors in regions without a template

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d. Errors due to misalignment e. Incorrect
templates
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Model Building Programs
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Applications
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Critical Assessment of protein Structure
Prediction (CASP)
Venclovas et al. Proteins, 2001
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Critical Assessment of protein Structure
Prediction (CASP)
Venclovas et al. Proteins, 2001
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Conclusions

• Computer Simulations are powerful to show
  detailed motions but they cannot cover long
  enough time spans to simulate folding for large
  systems
• Homology Modeling techniques can be successful if
  the target protein has a known fold
• The higher the sequence similarity the more
  likely the model will be successful
• With the implementation of better techniques the
  errors in fold assignment, alignment, and
  sidechain and loop modeling are decreasing
• Theoretically, if at least one member of every
  possible fold is known, it is possible to predict
  the structure of every coding sequence to within
  a certain accuracy