Homotopy Optimization Methods and Protein Structure Prediction Daniel M' Dunlavy Applied Mathematics

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Homotopy Optimization Methods and Protein
Structure PredictionDaniel M. Dunlavy Applied
Mathematics and Scientific ComputationUniversity
of Maryland, College Park
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Protein Structure Prediction
Amino Acid Sequence
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Protein Structure Prediction

• Given
• Protein model
• Properties of constituent particles
• Potential energy function (force field)
• Goal
• Predict native (lowest energy) conformation
• Thermodynamic hypothesis Anfinsen, 1973
• Develop hybrid method, combining
• Energy minimization numerical optimization
• Comparative modeling bioinformatics
• Use template (known structure) to predict target
  structure

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Protein Model Particle Properties

• Backbone model
• Single chain of particles with residue attributes
• Particles model C? atoms in proteins
• Properties of particles
• Hydrophobic, Hydrophilic, Neutral
• Diverse hydrophobic-hydrophobic interactions

Veitshans, Klimov, and Thirumalai. Protein
Folding Kinetics, 1996.
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Potential Energy Function
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Potential Energy Function
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Homotopy Optimization Method (HOM)

• Goal
• Minimize energy function of target protein
• Steps to solution
• Energy of template protein
• Define a homotopy function
• Deforms template protein into target protein
• Produce sequence of minimizers of
  starting at and ending at

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Energy Landscape Deformation Dihedral Terms
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Illustration of HOM
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Homotopy Optimization using Perturbations
Ensembles (HOPE)

• Improvements over HOM
• Produces ensemble of sequences of local
  minimizers of by perturbing
  intermediate results
• Increases likelihood of predicting global
  minimizer
• Algorithmic considerations
• Maximum ensemble size
• Determining ensemble members

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Illustration of HOPEMaximum ensemble size 2
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Numerical Experiments

• 9 chains (22 particles) with known structure

Loop Region
Sequence Homology ()
ABCDE F GH I
Hydrophobic Hydrophilic Neutral
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Numerical Experiments
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Numerical Experiments

• 62 template-target pairs
• 10 pairs had identical native structures
• Methods
• HOM vs. Newtons method w/trust region (N-TR)
• HOPE vs. simulated annealing (SA)
• Different ensemble sizes (2,4,8,16)
• Averaged over 10 runs
• Perturbations where sequences differ
• Measuring success
• Structural overlap function
• Percentage of interparticle distances off by more
  than 20 of the average bond length ( )
• Root mean-squared deviation (RMSD)

Ensemble SA Basin hopping T0 105 Cycles
10 Berkeley schedule
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Structural Overlap Function
Native
Predicted
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RMSD
Measures the distance between corresponding
particles in the predicted and lowest energy
conformations when they are optimally
superimposed.
where is a rotation and translation of
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Results
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Results

• Success of HOPE and SA with ensembles of size 16
  for each template-target pair. The size of each
  circle represents the percentage of successful
  predictions over the 10 runs.

SA
HOPE
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Conclusions

• Homotopy optimization methods
• More successful than standard minimizers
• HOPE
• For problems with
  readily available
• Solves protein structure prediction problem
• Outperforms ensemble-based simulated annealing
• Future work
• Protein Data Bank (templates), TINKER (energy)
• Convergence analysis for HOPE

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Acknowledgements

• Dianne OLeary (UM)
• Advisor
• Dev Thirumalai (UM), Dmitri Klimov (GMU)
• Model, numerical experiments
• Ron Unger (Bar-Ilan)
• Problem formulation
• National Library of Medicine (NLM)
• Grant F37-LM008162

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Thank You

• Daniel Dunlavy HOPE
• http//www.math.umd.edu/ddunlavy
• ddunlavy_at_math.umd.edu

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HOPE Algorithm
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Homotopy Parameter Functions

• Split low/high frequency dihedral terms
• Homotopy parameter functions for each term

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Homotopy Function for Proteins

• Different for individual energy terms

Template
Target