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SIMULATIONS OF PEPTIDE FOLDING and DYNAMICS

SIMULATIONS OF PEPTIDE FOLDING and DYNAMICS. Krzysztof Kuczera Departments of Chemistry and Molecular Biosciences University of Kansas. IMA Workshop Jan 14-18, 2008. Replica-exchange molecular dynamics. Propagate independent trajectories at temperatures T 1 > T 2 > T 3 …

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SIMULATIONS OF PEPTIDE FOLDING and DYNAMICS

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  1. SIMULATIONS OF PEPTIDE FOLDING and DYNAMICS Krzysztof Kuczera Departments of Chemistry and Molecular Biosciences University of Kansas IMAWorkshop Jan14-18, 2008

  2. Replica-exchange molecular dynamics Propagate independent trajectories at temperatures T1 > T2 > T3 … Stop and compare energies Exchange between neighbors T1 T2 T3 T4 D  0 D > 0 Advantages: + accelerated sampling @ low T + Boltzmann distributions @ all T + Minimal process communication

  3. 21-residue helix-forming peptide Blocked peptide: Ac-WAAAH+-(AAARA)3-A-NH2 21 residues Simulation 1: equilibrium distribution start: helix trajectory: 30 ns Simulation 2: folding start: extended trajectory: 15 ns Method: CHARMM with CMAP electrostatics: GBMV nonpolar: DGnp=- gDA with g = 4 cal/(mol Å2) REMD at 8 temperatures, 280-450 K MMTSB tool kit (C.L. Brooks, Scripps)

  4. Experiments: Gouri S. Jas BaylorUniversity • DH DS Tm • kcal/mol cal/(mol K) K • -12 -40 296 G.S. Jas & K. Kuczera, Biophys. J.,87:3786 (2004)

  5. Hydrogen bonds: HB: Oi…Ni+4 < 4.0 Å f = <NHB>/17 Backbone conformations: population of residues within 30o of (f,y) = (-62o,-41o) • DH DS Tm Data points with error bars: from 15-30 ns of REMD simulation Solid lines: from fit to van’t Hoff equation kcal/mol cal/(mol K) K REMD -10 -30 330-350 Experiment -12 -40 296

  6. Zimm-Bragg Parameters Statistical weights partition function coil : 1 helix with h-bond: w = s helix without h-bond: v = s 1/2 REMD results at 300 K: helix fraction = 0.78 number of helix fragments = 1.08 w = 1.86 v = 0.11 Previous Ala-based peptide simulations: w = 1.12 – 2.12 v = 0.06 – 0.30

  7. Equilibrium f-y distribution 300 K 450 K

  8. a-helix (f,y) = (-62o,-41o) PPII (f,y) = (-78o,149o) b-strand (f,y) = (-139o,145o)

  9. Folding: transition state w(n) = -kTln[P(n)/C(n)] C(n) = 17!/n!(17-n)! w(n) = -kTln[P(n)]

  10. Equilibrium REMD: conclusions • We have calculated an equilibrium melting curve • for a helix-forming peptide with GB/SA model • Thermodynamics qualitatively correct • Melting temperature exaggerated • Global free energy minimum • = a-helixat low T • = coil at high T • Microscopic information about helix unfolding • - unfolding initiated at termini • transition state  ½ helix • - formation of compact structures at low T • - b and PPII structures at high T

  11. REMD simulation of helix folding Ideal a-helix appears after 2.8 ns

  12. Folding REMD: conclusions • a-helix structure found after ca. 3 ns simulation time • confirm that helix is global FE minimum, • not a memory effect • folding in room T replica is sequential • structures and properties sampled are similar to • trajectory starting from helix • conformational sampling acceleration of REX-MD • over direct MD is ca. 100 overall (ca. 12per CPU)  • [3 ns folding in REMD vs. 300 ns exp time scale]

  13. Acknowledgments • Gerald Lushington, University of Kansas Molecular • Modeling and Graphics Laboratory – Athlon cluster • Michael Feig, John Caranicolas and Charles L. Brooks III • MMTSB Tool Set (2001), The Scripps Research Institute • Gouri S. Jas, Baylor University - experiments • ACS PRF $$$

  14. DH DS Tm kcal/mol cal/(mol K) K REMD -10 -30 330-350 Experiment -12 -40 296 w(n) = -kT ln P(n)

  15. REMD simulation of helix-coil equilibrium Replica-exchange MD: Propagate independent trajectories at temperatures T1 > T2 > T3 … Stop and compare energies Exchange between neighbors T1 T2 T3 T4

  16. DH DS Tm • kcal/mol cal/(mol K) K • Exp -12 -40 296 • REMD f/y -7 -20 354 • REMD hbonds -10 -27 354

  17. w(n) = -kT ln P(n)

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