simulations of peptide folding and dynamics
DESCRIPTION
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 … - PowerPoint PPT PresentationTRANSCRIPT
SIMULATIONS OF PEPTIDEFOLDING and DYNAMICS
Krzysztof Kuczera
Departments of Chemistry and Molecular BiosciencesUniversity of Kansas
IMAWorkshop Jan14-18, 2008
Replica-exchange molecular dynamics
T1
T2
T3
T4
Propagate independenttrajectories at temperaturesT1 > T2 > T3 …Stop and compare energiesExchange between neighbors
ii
jiij
kT
EE
ejiw
jiw
1
))((
)(
1)(
Advantages:+ accelerated sampling @ low T+ Boltzmann distributions @ all T+ Minimal process communication
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: Gnp=- A with = 4 cal/(mol Å2)
REMD at 8 temperatures, 280-450 K
MMTSB tool kit (C.L. Brooks, Scripps)
Sm
kcal/mol cal/(mol K) K
-12 -40 296G.S. Jas & K. Kuczera, Biophys. J., 87:3786 (2004)
Experiments:Gouri S. JasBaylor University
Sm
kcal/mol cal/(mol K) K
REMD -10 -30 330-350Experiment -12 -40 296
Hydrogen bonds:HB: Oi…Ni+4 < 4.0 Å f = <NHB>/17
Backbone conformations:population of residues within 30o of () = (-62o,-41o)
Data points with error bars: from 15-30 ns of REMD simulationSolid lines: from fit to van’t Hoff equation
Zimm-Bragg ParametersStatistical weights partition function coil : 1 helix with h-bond: w = s helix without h-bond: v = 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
Equilibrium distribution 300 K 450 K
helix
PPII
strand
Folding: transition state
w(n) = -kTln[P(n)]w(n) = -kTln[P(n)/C(n)]
C(n) = 17!/n!(17-n)!
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 = -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 - and PPII structures at high T
REMD simulation of helix folding
Ideal -helix appears after 2.8 ns
Folding REMD: conclusions
• -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. 12per CPU) [3 ns folding in REMD vs. 300 ns exp time scale]
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 $$$
w(n) = -kT ln P(n)
Sm
kcal/mol cal/(mol K) K
REMD -10 -30 330-350Experiment -12 -40 296
T1
T2
T3
T4
Replica-exchange MD:Propagate independenttrajectories at temperaturesT1 > T2 > T3 …Stop and compare energiesExchange between neighbors
REMD simulation of helix-coil equilibrium
Sm
kcal/mol cal/(mol K) K
Exp -12 -40 296
REMD -7 -20 354
REMD hbonds -10 -27 354
w(n) = -kT ln P(n)