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Using two recently-developed molecular dynamics protocols for protein folding

Using two recently-developed molecular dynamics protocols for protein folding. Timothy H. Click Department of Chemistry and Biochemistry University of Oklahoma Norman, Oklahoma. Outline. Introduction to MD protocols Previous work Simulations of tryptophan zipper 2

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Using two recently-developed molecular dynamics protocols for protein folding

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  1. Using two recently-developed molecular dynamics protocols for protein folding Timothy H. Click Department of Chemistry and Biochemistry University of Oklahoma Norman, Oklahoma

  2. Outline • Introduction to MD protocols • Previous work • Simulations of tryptophan zipper 2 • Simulation of Streptococcal protein G B1 domain (residues 41-56) • Conclusions • Future directions • Acknowledgements

  3. Protein geometry optimization Dill, K.A.; Chan, H.S. Nat. Struct. Biol., 1997, 4, 10-19.

  4. 1st MD protocol — DIVE • Disrupted Velocity (DIVE) search protocol • Velocity reassignment of coordinate histories • Magnitude rescaling — energy perturbation • Direction changes • Reassignment every n steps (defined by user) • Heating and cooling cycles • Conformations sampled near absolute zero • Overall, protocol disrupts equilibrium • Energy barriers overcome or circumvented • Several potential energy minima sampled

  5. How conformations are selected β βlow to DIP βlow βlow2 to DIP

  6. 2nd MD protocol — DIP • Divergent Path (DIP) search strategy • Coordinate histories at same constant temperature • Simulations involve multiple coordinate histories • Individual coordinate histories randomly assigned initial velocities • Velocities can be altered allowing for different conditions • Constant temperatures maintained by rescaling velocity magnitudes • Broader sampling of potential energy surface allowed

  7. DIP simulation

  8. DIP simulation (cont’d) <E>= -624.22 ± 8.27 kcal/mol <RMSD> = 1.6 ± 0.5 Å <E>= -632.42 ± 8.44 kcal/mol <RMSD> = 1.8 ± 0.2 Å <E>= -587.16 ± 9.50 kcal/mol <RMSD> = 13.2 ± 0.5 Å <E>= -633.94 ± 7.87 kcal/mol <RMSD>= 1.5 ± 0.2 Å nmr <E>= -592.02 ± 8.38 kcal/mol <RMSD> = 12.5 ± 0.5 Å <E>= -600.29 ± 13.05 kcal/mol <RMSD> = 11.3 ± 0.7 Å

  9. Protocol procedures • Modified Amber force field (Okur,A.; Strockbine, B.; Hornak, V.; Simmerling, C., J. Comput. Chem., 2003, 21) • Constraints on atoms covalently bonded to hydrogen • Implicit solvent • 2 fs time step • 4,000,000 steps • Velocity disruption every 20,000 steps (DIVE) • T = 300 ± 20 K (DIP) • 6 independent coordinate histories/simulation

  10. Previous work with α-helices • Zunnan Huang • 13-residue polyalanine • Trp-cage (α-helix and 310-helix • Huang and Zhanyong Guo • Peptide F • Timothy H. Click • C-peptide of ribonuclease A (residues 1-13)

  11. Tryptophan zipper 2 (trpzip2) • De novo 12-residue polypeptide • Sequence (S1WTWENGKWTWK12-NH2) • PDB code 1LE1 (20 NMR models) • Stable β-sheet in aqueous solution by cross-stranded pairs of four tryptophans • Simulations completed by other groups 1 Cochran, A.G.; Skelton, N.J.; Starovasnik, M.A. P. Natl. Acad. Sci. USA, 2001, 98, 5578-5583.

  12. Trpzip2 DIVE Results extlow E = -496.59 kcal/mol RMSD 6.9 Ẳ βlow E = -494.05 kcal/mol RMSD 5.0 Ẳ αlow E = -498.22 kcal/mol RMSD 6.1 Ẳ β* E = -489.44 kcal/mol RMSD 0.9 Ẳ extlow2 E = -499.23 kcal/mol RMSD 7.0 Ẳ βlow2 E = -497.06 kcal/mol RMSD 5.7 Ẳ αlow2 E = -498.17 kcal/mol RMSD 6.1 Ẳ

  13. Trpzip2 DIP Results ext <E> = -360.82 ± 7.66 kcal/mol <RMSD> 6.5 ± 0.8 Ẳ β <E> = -381.65 ± 4.55 kcal/mol <RMSD> 0.9 ± 0.1 Ẳ α <E> = -369.79 ± 9.01 kcal/mol <RMSD> 6.7 ± 0.4 Ẳ extlow <E> = -375.47 ± 6.28 kcal/mol <RMSD> 7.5 ± 0.1 Ẳ βlow <E> = -374.14 ± 7.18 kcal/mol <RMSD> 7.0 ± 0.3 Ẳ αlow <E> = -368.77 ± 7.38 kcal/mol <RMSD> 6.1 ± 0.1 Ẳ β* <E> = -381.65 ± 5.04 kcal/mol <RMSD> 0.8 ± 0.1 Ẳ extlow2 <E> = -381.44 ± 5.74 kcal/mol <RMSD> 7.4 ± 0.1 Ẳ βlow2 <E> = -378.75 ± 6.04 kcal/mol <RMSD> 7.0 ± 0.3 Ẳ αlow2 <E> = -368.93 ± 7.54 kcal/mol <RMSD> 6.2 ± 0.3 Ẳ

  14. Trpzip2 Summary • PES rough at low temperatures • β-hairpin challenging secondary structure • β-hairpin as relative global PE conformation • α-helices metastable conformation

  15. B1 domain of Streptococcal protein G • Natural β-hairpin stable in aqueous solution. • Sequence (G41EWTYDDATKTFTVTE56) • PDB 2GB1 (x-ray crystal structure) • Stabilization factors • Hydrophobic core • Terminal salt bridge • Several simulations 2 Gronenborn, A. M.; Filpula, D. R.; Essig, N. Z.; Achari, A.; Whitlow, M.; Wingfield, P. T.; Clore, G. M. Science, 1991, 253, 657-661.

  16. Protein G DIVE results extlow E = -784.40 kcal/mol RMSD 7.4 Ẳ βlow E = -774.96 kcal/mol RMSD 6.8 Ẳ αlow E = -783.53 kcal/mol RMSD 8.4 Ẳ β* E = -770.54 kcal/mol RMSD 0.9 Ẳ extlow2 E = -785.85 kcal/mol RMSD 7.3 Ẳ βlow2 E = -781.75 kcal/mol RMSD 6.4 Ẳ αlow2 E = -785.64 kcal/mol RMSD 8.4 Ẳ

  17. Protein G DIP results ext <E> = -612.63 ± 9.31 kcal/mol <RMSD> 10.6 ± 0.6 Ẳ β <E> = -638.42 ± 5.84 kcal/mol <RMSD> 1.6 ± 0.4 Ẳ α <E> = -646.18 ± 6.90 kcal/mol <RMSD> 8.9 ± 0.2 Ẳ extlow <E> = -640.60 ± 7.13 kcal/mol <RMSD> 9.1 ± 0.3 Ẳ βlow <E> = -651.05 ± 6.34 kcal/mol <RMSD> 6.9 ± 1.2 Ẳ αlow <E> = -646.14 ± 6.01 kcal/mol <RMSD> 9.0 ± 0.3 Ẳ β* <E> = -644.28 ± 6.08 kcal/mol <RMSD> 1.6 ± 0.2 Ẳ extlow2 <E> = -633.74 ± 7.13 kcal/mol <RMSD> 9.0 ± 0.7 Ẳ βlow2 <E> = -643.91 ± 7.86 kcal/mol <RMSD> 9.0 ± 0.3 Ẳ αlow2 <E> = -650.14 ± 6.33 kcal/mol <RMSD> 9.0 ± 0.2 Ẳ

  18. Protein G summary • β-hairpin stable at 300 K • Helical conformation lower in energy • Better energy compensation3 • Agreement with other simulation4 • Various factors may overstabilize helices (e.g., implicit solvent, salt bridges) 3 Muñoz, V.; Thompson, P. A.; Hofrichter, J.; Eaton, W. A. Nature, 1997, 390, 196-199. 4 Krivov, S. V.; Karplus, M. P. Natl. Acad. Sci., USA, 2004, 101, 14766-14770.

  19. Conclusions • DIVE and DIP locate several PE minima • PES mapped by DIVE • PES of conformations at desired temperature with DIP • Conformations in good, if not excellent, agreement with experimental structures using DIP and DIVE

  20. Future directions • Continue validation of MD protocols with larger β-sheet • Further test MD protocols with tertiary structure • Predict structure of small protein

  21. Acknowledgements • Ralph A. Wheeler • Zunnan Huang and Adam Hixson • National Research Service Award 5 F31 GM067560-03 to THC from the NIH/NIGMS • Oklahoma Center for the Advancement of Science and Technology (OCAST) HR01-148 • Oklahoma Supercomputing Center for Education and Research (OSCER) • NSF/NRAC supercomputer time MCA96-N019

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