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An improved all-atom force field with implicit solvation for folding simulations of small proteins

An improved all-atom force field with implicit solvation for folding simulations of small proteins. Eunae Kim and Youngshang Pak. Department of Chemistry, Pusan National University. Our current research. 2. Folding studies using MD with all-atom level force field with implicit solvation.

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An improved all-atom force field with implicit solvation for folding simulations of small proteins

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  1. An improved all-atom force field with implicit solvation for folding simulations of small proteins Eunae Kim and Youngshang Pak Department of Chemistry, Pusan National University

  2. Our current research 2. Folding studies using MD with all-atom level force field with implicit solvation. 1. Development of novel simulation schemes

  3. Force field in protein folding • Protein force field : united to all-atom models • Solvation model : explicit water and implicit water models

  4. Is the current all-atom force field good enough for protein folding simulation? Not really !

  5. Case1: Comparisons of force fields for Alpha helix C-peptide and Hairpin G-peptide in explicit water * Initial structure : unfolding state C-peptide using REMUCA G-peptide using MUCAREM Takao et al, Chem. Phys. Lett. (2004) 386, 460

  6. Lesson I With explicit solvation, alpha/beta imbalances exist.

  7. B Radius of gyration (Å) A C N RMSD (Å) Case 2: REMD simulation of 1PSV using param99MOD2 with the GB implicit water Pak et al, J. Chem. Phys. (2004) 121, 9184

  8. C-terminal C-terminal C-terminal N-terminal 28R 28R 28R N-terminal 24T 23E 23E 24T 23E 20D 6R 20D 10R 19R 20D 17E 19R 4T 10R 19R 17E 17E 13S 15E 13S N-terminal The current GB solvation model has a problem ! → The salt bridge effect is overestimated by the GBSA model

  9. Lesson II With implicit solvation, 1. alpha/beta imbalances exist. 2. The salt bridge effects are overestimated by the GB solvation.

  10. For all-atom force field with GB solvation, native state should be the lowest free energy minimum with reasonable energy barriers. Our immediate goal

  11. GB intrinsic radii of the formally charged group 1 Protein backbone parameters 2 Proposal : • To achieve our immediate goal, adjusting all-atom force field with the GB implicit solvation: Fine tuning these!

  12. GBOBCI : α = 0.8, β = 0.0, γ = 2.910 ρi : intrinsic radii of atom i (from modified Bondi radii) The Generalized Born Model • Proteins 55, 383 (2004), David A. Case Where In order to weaken the overestimated salt bridge effect by the current GB model, we currently propose as follows:  We employ scaling ρiof the functional groups of charged side-chains and hydroxyl oxygen byα = 0.85.

  13. Force field optimization

  14. Replica Exchange Molecular Dynamics

  15. param99MOD3 The backbone torsional potential parameters should be further modified for more balanced description of ββαmotifs (a training set of 1FSD, 1PSV and BBA5) → Formation of the β-strand is enhanced by the scheme in α/β peptides

  16. REMD with our new force field • Initial structure : Folded structure • In REMD, 20 replicas were run in parallel at the 250 ~ 620 K with TINKER package → The temperature gap in REM • Total running time : 50 ns • Time step : 2 fs • Exchange interval : 500 fs • Trajectory saving interval : 500 fs • Force field : param99MOD3 • Solvation model : the modified GB model (Case et al. & scaling factor, α=0.85) • Cutoff : 24.0 Å (the nonbond and GB solvation terms) • Integrate :velocity Verlet • Friction : 1.0 ps-1 • SHAKE algorithm

  17. Free energy landscapes BBA5 1PSV 1FSD Pak et al, Proteins (2006) 62, 663

  18. Direct folding studies of α or βstrands C-peptide EK-peptide gb1 1e0q Pak et al, Proteins (2006) in press.

  19. Temperature dependence

  20. Direct folding studies of ββα motifs 1FSD 1PSV

  21. 1PSV 1FSD RMSD = 1.8 Å RMSD = 2.0 Å The predicted lowest free energy conformer (blue) NMR structure (gray) Pak et al, Biophys. J. submitted.

  22. Problems of param99MOD3 • TheP state of gb1 is lower than the F state in free energy.(~0.3 kcal/mol) (In explicit solvent, F state < P state : Zhou, PNAS (2003) 100, 13280.) • Incorrect location of the native structure of trp-cage (1l2y: 23-residue βα protein)

  23. param99MOD4(1PSV, 1FSD, BBA5, gb1, 1l2y) Table I. Parameter sets used in the various modified GB Implementations GBOBCII : α = 1.0, β = 0.8, γ = 4.85 ρi: intrinsic radii of atom i

  24. param99MOD4

  25. gb1 Tm = 22°C (Expt. Tm = 24°C) ∆H = 48 kJ/mol , ∆S = 162 J/mol (F -> U) ∆H = 49 kJ/mol , ∆S = 163 J/mol (expt.)

  26. Trp-cage (1l2Y) Tm = 41°C (Expt. Tm = 42°C) ∆H = 48 kJ/mol , ∆S = 148 J/mol (F -> U) ∆H = 49 kJ/mol , ∆S = 155 J/mol (expt.)

  27. The simulations for 1FSD, 1PSV, and BBA5 are still underway…, but they look promising!

  28. Conclusions • Our new force fields (MOD3 and MOD4) show very significant improvement in folding simulation of small proteins: More reasonable free energy landscapes 1 2 Correct thermodynamic properties

  29. Future work • United atom model (ff03ua) in AMBER9 will be improved using the current scheme. • Free energy mapping and direct folding of more complicated proteins GB1

  30. Acknowledgments • 학술진흥재단 • BK21 • KISTI

  31. Group members • Eunae Kim (Ph. D.) • Changwon Yang (M.S.)

  32. Thanks for attention !!

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