Bioinformatics: Practical Application of Simulation and Data Mining Markov Modeling II

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Bioinformatics Practical Application of
Simulation and Data MiningMarkov Modeling II

• Prof. Corey OHern
• Department of Mechanical Engineering
• Department of Physics
• Yale University

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Markov Modeling of Proteins
Describing protein folding kinetics by Molecular
Dynamics Simulations. 1. Theory W. C. Swope, J.
W. Pitera, and F. Suits, J. Phys. Chem. B 108
(2004) 6571.
Describing protein folding kinetics by Molecular
Dynamics Simulations. 2. Example applications to
Alanine Dipeptide and a ?-hairpin peptide W. C.
Swope, J. W. Pitera, et al., J. Phys. Chem. B
108 (2004) 6582.
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I. Alanine Dipeptide
6 backbone atoms 3 dihedral angles (?, ?, ?)
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Macrostate Definition
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T500K
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5
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Kinetics at T500 K

• 10,000 separate trajectories sampled 200 times at
• 0.5ps intervals (100ps) using AMBERShake

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MS Lifetime Distributions
MS1
MS5
1/(1-Tii)
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Transition Matrix Eigenvalues
?F 550ps
Markovian
Non- Markovian
spurious
?F gtgt tkin 100ps
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II. ?-hairpin motif of protein G
G41EWTYDDATKTFTVTE56
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Hydrogen bonding
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Macrostate Definition

• 287 conformations run at NVE (310 K) for 0.5 ns
• using explicit water and Na counterions
• Order parameters Rg, number and order of
• hydrogen bonds

Hydrogen bonds
Radius of gyration
000000
turn
termini
111111
S,M,L,E
000001
00011X
264?22-35 macrostates
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MS Lifetime Distributions
Non-Markovian
Markovian gt 50ps
000000E
00111X
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Transition Matrix Eigenvalues
Time reversed
Non- Markovian
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Predicted Folding Time
?F 20 ns ltlt 6 ?s

• Short 0.5 ns trajectories (4 orders
• of magnitude difference)
• 2. Long-lived conformations

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Long-lived Conformations
Misregistered H-bonds
Misregistered H-bonds
splayed, ion association
misformed turn
tight turn
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Using massively parallel simulation and
Markovian Models to study protein folding
Examining the dynamics Of the villin headpiece,
J. Chem. Phys. 124 (2006) 164902.
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Villin headpiece-HP-36
MLSDEDFKAVFGMTRSAFANLPLWKQQNLKKEKGLF PDB 1 VII
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Simulation Details
50,000 trajectories 10ns/trajectory 500 ?s

• Gromacs with explicit solvent (5000 water
  molecules)
• and eight counterions Amber bond constraints

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Native State Ensemble
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