Molecular-dynamics simulations are increasingly used to study dynamic properties of biological systems. With this development, the ability of force fields to successfully predict relaxation timescales and the associated conformational exchange processes moves into focus. We assess to what extent the dynamic properties of model peptides (Ac-A-NHMe, Ac-V-NHMe, AVAVA, A10) differ when simulated with different force fields (AMBER ff99SB-ILDN, AMBER ff03, OPLS-AA/L, CHARMM27, and GROMOS43a1). The dynamic properties are extracted using Markov state models. For single-residue models (Ac-A-NHMe, Ac-V-NHMe), the slow conformational exchange processes are similar in all force fields, but the associated relaxation timescales differ by up to an order of magnitude. For the peptide systems, not only the relaxation timescales, but also the conformational exchange processes differ considerably across force fields. This finding calls the significance of dynamic interpretations of molecular-dynamics simulations into question.
REFERENCES
1.
Y.
Duan
and P. A.
Kollman
, “Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution
,” Science
282
, 740
(1998
).2.
R. H.
Swendsen
and J.-S.
Wang
, “Replica Monte Carlo simulation of spin-glasses
,” Phys. Rev. Lett.
57
, 2607
–2609
(1986
).3.
Y.
Sugita
and Y.
Okamoto
, “Replica exchange molecular dynamics method for protein folding simulation
,” Chem. Phys. Lett.
314
, 141
–151
(1999
).4.
J.
Graf
, P. H.
Nguyen
, G.
Stock
, and H.
Schwalbe
, “Structure and dynamics of the homologous series of alanine peptides: A joint molecular dynamics/NMR study
,” J. Am. Chem. Soc.
129
, 1179
–1189
(2007
).5.
R. B.
Best
, N.-V.
Buchete
, and G.
Hummer
, “Are current molecular dynamics force fields too helical?
,” Biophys. J.
95
, L07
–L09
(2008
).6.
F.
Jiang
, W.
Han
, and Y.-D.
Wu
, “Influence of side chain conformations on local conformational features of amino acids and implication for force field development
,” J. Phys. Chem. B.
114
, 5840
–5850
(2010
).7.
F.
Jiang
, W.
Han
, and Y.-D.
Wu
, “The intrinsic conformational features of amino acids from a protein coil library and their applications in force field development
,” Phys. Chem. Chem. Phys.
15
, 3413
–3428
(2013
).8.
E. A.
Cino
, W.-Y.
Choy
, and M.
Karttunen
, “Comparison of secondary structure formation using 10 different force fields in microsecond molecular dynamics simulations
,” J. Chem. Theory Comput.
8
, 2725
–2740
(2012
).9.
S.
Gnanakaran
and A. E.
García
, “Helix-coil transition of alanine peptides in water: Force field dependence on the folded and unfolded structures
,” Proteins: Struct., Funct., Genet.
59
, 773
–782
(2005
).10.
R. B.
Best
and G.
Hummer
, “Optimized molecular dynamics force fields applied to the helix-coil transition of polypeptides
,” J. Phys. Chem. B
113
, 9004
–9015
(2009
).11.
G. A.
Kaminski
, R. A.
Friesner
, J.
Tirado-Rives
, and W. L.
Jorgensen
, “Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides
,” J. Phys. Chem. B
2
, 6474
–6487
(2001
).12.
V.
Hornak
, R.
Abel
, A.
Okur
, B.
Strockbine
, A.
Roitberg
, and C.
Simmerling
, “Comparison of multiple Amber force fields and development of improved protein backbone parameters
,” Proteins: Struct., Funct., Genet.
65
, 712
–725
(2006
).13.
A. D.
MacKerell
, N.
Banavali
, and N.
Foloppe
, “Development and current status of the CHARMM force field for nucleic acids
,” Biopolymers
56
, 257
–265
(2001
).14.
A. D.
MacKerell
, M.
Feig
, and C. L.
Brooks
, “Improved treatment of the protein backbone in empirical force fields
,” J. Am. Chem. Soc.
126
, 698
–699
(2004
).15.
K.
Lindorff-Larsen
, S.
Piana
, K.
Palmo
, P.
Maragakis
, J. L.
Klepeis
, R. O.
Dror
, and D. E.
Shaw
, “Improved side-chain torsion potentials for the Amber ff99SB protein force field
,” Proteins: Struct., Funct., Bioinf.
78
, 1950
–1958
(2010
).16.
K. A.
Beauchamp
, Y.-S.
Lin
, R.
Das
, and V. S.
Pande
, “Are protein force fields getting better? A systematic benchmark on 524 diverse NMR measurements
,” J. Chem. Theory Comput.
8
, 1409
–1414
(2012
).17.
R. B.
Best
, X.
Zhu
, J.
Shim
, P. E. M.
Lopes
, J.
Mittal
, M.
Feig
, and A. D.
Mackerell
, “Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone ϕ, ψ and side-chain χ (1) and χ (2) dihedral angles
,” J. Chem. Theory Comput.
8
, 3257
–3273
(2012
).18.
C.
Oostenbrink
, A.
Villa
, A. E.
Mark
, and W. F.
van Gunsteren
, “A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6
,” J. Comput. Chem.
25
, 1656
–1676
(2004
).19.
O. F.
Lange
, D.
van der Spoel
, and B. L.
de Groot
, “Scrutinizing molecular mechanics force fields on the submicrosecond timescale with NMR data
,” Biophys. J.
99
, 647
–655
(2010
).20.
K.
Lindorff-Larsen
, P.
Maragakis
, S.
Piana
, M. P.
Eastwood
, R. O.
Dror
, and D. E.
Shaw
, “Systematic validation of protein force fields against experimental data
,” PloS One
7
, e32131
(2012
).21.
J. L.
Klepeis
, K.
Lindorff-Larsen
, R. O.
Dror
, and D. E.
Shaw
, “Long-timescale molecular dynamics simulations of protein structure and function
,” Curr. Opin. Struct. Biol.
19
, 120
–127
(2009
).22.
D. E.
Shaw
, P.
Maragakis
, K.
Lindorff-Larsen
, S.
Piana
, R. O.
Dror
, M. P.
Eastwood
, J. A.
Bank
, J. M.
Jumper
, J. K.
Salmon
, Y.
Shan
, and W.
Wriggers
, “Atomic-level characterization of the structural dynamics of proteins
,” Science
330
, 341
–346
(2010
).23.
F.
Noé
, C.
Schütte
, E.
Vanden-Eijnden
, L.
Reich
, and T. R.
Weikl
, “Constructing the equilibrium ensemble of folding pathways from short off-equilibrium simulations
,” Proc. Natl. Acad. Sci. U. S. A.
106
, 19011
–19016
(2009
).24.
T. J.
Lane
, G. R.
Bowman
, K.
Beauchamp
, V. A.
Voelz
, and V. S.
Pande
, “Markov state model reveals folding and functional dynamics in ultra-long MD trajectories
,” J. Am. Chem. Soc.
133
, 18413
–18419
(2011
).25.
K.
Lindorff-Larsen
, S.
Piana
, R. O.
Dror
, and D. E.
Shaw
, “How fast-folding proteins fold
,” Science
334
, 517
–520
(2011
).26.
K. A.
Beauchamp
, R.
McGibbon
, Y.-S.
Lin
, and V. S.
Pande
, “Simple few-state models reveal hidden complexity in protein folding
,” Proc. Natl. Acad. Sci. U. S. A.
109
, 17807
–17813
(2012
).27.
A. K.
Faradjian
and R.
Elber
, “Computing time scales from reaction coordinates by milestoning
,” J. Chem. Phys.
120
, 10880
–10889
(2004
).28.
P. G.
Bolhuis
, D.
Chandler
, C.
Dellago
, and P. L.
Geissler
, “Transition path sampling: Throwing ropes over rough mountain passes, in the dark
,” Annu. Rev. Phys. Chem.
53
, 291
–318
(2002
).29.
W. F.
van Gunsteren
, R.
Bürgi
, C.
Peter
, and X.
Daura
, “The key to solving the protein-folding problem lies in an accurate description of the denatured state
,” Angew. Chem., Int. Ed. Engl.
40
, 351
–355
(2001
).30.
P. L.
Freddolino
, S.
Park
, B.
Roux
, and K.
Schulten
, “Force field bias in protein folding simulations
,” Biophys. J.
96
, 3772
–3780
(2009
).31.
B.
Keller
, Z.
Gattin
, and W. F.
van Gunsteren
, “What stabilizes the 3(14)-helix in beta3-peptides? A conformational analysis using molecular simulation
,” Proteins: Struct., Funct., Bioinf.
78
, 1677
–1690
(2010
).32.
S.
Piana
, K.
Lindorff-Larsen
, and D. E.
Shaw
, “How robust are protein folding simulations with respect to force field parameterization?
,” Biophys. J.
100
, L47
–L49
(2011
).33.
W. C.
Swope
, J. W.
Pitera
, and F.
Suits
, “Describing protein folding kinetics by molecular dynamics simulations. 1. Theory
,” J. Phys. Chem. B
108
, 6571
–6581
(2004
).34.
J. D.
Chodera
, N.
Singhal
, V. S.
Pande
, K.
Dill
, and W. C.
Swope
, “Automatic discovery of metastable states for the construction of Markov models of macromolecular conformational dynamics
,” J. Chem. Phys.
126
, 155101
(2007
).35.
F.
Noé
, I.
Horenko
, C.
Schütte
, and J. C.
Smith
, “Hierarchical analysis of conformational dynamics in biomolecules: Transition networks of metastable states
,” J. Chem. Phys
126
, 155102
(2007
).36.
N.-V.
Buchete
and G.
Hummer
, “Coarse master equations for peptide folding dynamics
,” J. Phys. Chem. B
112
, 6057
–6069
(2008
).37.
J.-H.
Prinz
, H.
Wu
, M.
Sarich
, B.
Keller
, M.
Senne
, M.
Held
, J. D.
Chodera
, C.
Schütte
, and F.
Noé
, “Markov models of molecular kinetics: Generation and validation
,” J. Chem. Phys.
134
, 174105
(2011
).38.
B.
Keller
, P.
Hünenberger
, and W. F.
van Gunsteren
, “An analysis of the validity of Markov state models for emulating the dynamics of classical molecular systems and ensembles
,” J. Chem. Theory Comput.
7
, 1032
–1044
(2011
).39.
J. D.
Chodera
and F.
Noé
, “Markov state models of biomolecular conformational dynamics
,” Curr. Opin. Struct. Biol.
25
, 135
–144
(2014
).40.
F.
Noé
, S.
Doose
, I.
Daidone
, M.
Löllmann
, M.
Sauer
, J. D.
Chodera
, and J. C.
Smith
, “Dynamical fingerprints for probing individual relaxation processes in biomolecular dynamics with simulations and kinetic experiments
,” Proc. Natl. Acad. Sci. U. S. A.
108
, 4822
–4827
(2011
).41.
B. G.
Keller
, J.-H.
Prinz
, and F.
Noé
, “Markov models and dynamical fingerprints: Unraveling the complexity of molecular kinetics
,” Chem. Phys.
396
, 92
–107
(2012
).42.
J. D.
Chodera
, W. C.
Swope
, J. W.
Pitera
, and K. A.
Dill
, “Longtime protein folding dynamics from shorttime molecular dynamics simulations
,” Multiscale Model. Simul.
5
, 1214
–1226
(2006
).43.
D. S.
Chekmarev
, T.
Ishida
, and R. M.
Levy
, “Long-time conformational transitions of alanine dipeptide in aqueous solution: Continuous and discrete-state kinetic models
,” J. Phys. Chem. B
108
, 19487
–19495
(2004
).44.
P. G.
Bolhuis
, C.
Dellago
, and D.
Chandler
, “Reaction coordinates of biomolecular isomerization
,” Proc. Natl. Acad. Sci. U. S. A.
97
, 5877
–5882
(2000
).45.
C. A. F.
de Oliveira
, D.
Hamelberg
, and J. A.
McCammon
, “Estimating kinetic rates from accelerated molecular dynamics simulations: Alanine dipeptide in explicit solvent as a case study
,” J. Chem. Phys
127
, 175105
(2007
).46.
W.-N.
Du
, K. A.
Marino
, and P. G.
Bolhuis
, “Multiple state transition interface sampling of alanine dipeptide in explicit solvent
,” J. Phys. Chem.
135
, 145102
(2011
).47.
X.
Daura
, A. E.
Mark
, and W. F.
van Gunsteren
, “Parametrization of aliphatic CH n united atoms of GROMOS96 force field
,” J. Comput. Chem.
19
, 535
–547
(1998
).48.
W. R. P.
Scott
, P. H.
Hünenberger
, I. G.
Tironi
, A. E.
Mark
, S. R.
Billeter
, J.
Fennen
, A. E.
Torda
, T.
Huber
, P.
Krüger
, and W. F.
van Gunsteren
, “The GROMOS biomolecular simulation program package
,” J. Phys. Chem. A
103
, 3596
–3607
(1999
).49.
Y.
Duan
, C.
Wu
, S.
Chowdhury
, M. C.
Lee
, G.
Xiong
, W. E. I.
Zhang
, R.
Yang
, P.
Cieplak
, R. A. Y.
Luo
, T.
Lee
, J.
Caldwell
, J.
Wang
, and P.
Kollman
, “A point-charge force field for molecular mechanics quantum mechanical calculations
,” J. Comput. Chem.
24
, 1999
–2012
(2003
).50.
See supplementary material at http://dx.doi.org/10.1063/1.4909549 for model validation and further analysis.
51.
M.
Sarich
, F.
Noé
, and C.
Schütte
, “On the approximation quality of Markov state models
,” Multiscale Model. Simul.
8
, 1154
–1177
(2010
).52.
D.
Van Der Spoel
, E.
Lindahl
, B.
Hess
, G.
Groenhof
, A. E.
Mark
, and H. J. C.
Berendsen
, “GROMACS: Fast, flexible, and free
,” J. Comput. Chem.
26
, 1701
–1718
(2005
).53.
W. L.
Jorgensen
, J.
Chandrasekhar
, J. D.
Madura
, R. W.
Impey
, and M. L.
Klein
, “Comparison of simple potential functions for simulating liquid water
,” J. Chem. Phys.
79
, 926
(1983
).54.
W. L.
Jorgensen
, D. S.
Maxwell
, and J.
Tirado-Rives
, “Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids
,” J. Am. Chem. Soc.
7863
, 11225
–11236
(1996
).55.
H. J. C.
Berendsen
, J. R.
Grigera
, and T. P.
Straatsma
, “The missing term in effective pair potentials
,” J. Phys. Chem.
91
, 6269
–6271
(1987
).56.
J. C.
Kendrew
, R. E.
Dickerson
, B. E.
Strandberg
, R. G.
Hart
, D. R.
Davies
, D. C.
Phillips
, and V. C.
Shore
, “Structure of myoglobin: A three-dimensional Fourier synthesis at 2 Å resolution
,” Nature
185
, 422
–427
(1960
).57.
D. S.
Kosov
and G.
Stock
, “Conformational dynamics of trialanine in water. 2. Comparison of AMBER, CHARMM, GROMOS, and OPLS force fields to NMR and infrared experiments
,” J. Phys. Chem. B
107
, 5064
–5073
(2003
).58.
T.
Yoda
, Y.
Sugita
, and Y.
Okamoto
, “Comparisons of force fields for proteins by generalized-ensemble simulations
,” Chem. Phys. Lett.
386
, 460
–467
(2004
).59.
S.
Marqusee
, V. H.
Robbins
, and R. L.
Baldwin
, “Unusually stable helix formation in short alanine-based peptides
,” Proc. Natl. Acad. Sci. U. S. A.
86
, 5286
–5290
(1989
).60.
S.
Williams
, T. P.
Causgrove
, R.
Gilmanshin
, K. S.
Fang
, R. H.
Callender
, W. H.
Woodruff
, and R. B.
Dyer
, “Fast events in protein folding: Helix melting and formation in a small peptide
,” Biochemistry
35
, 691
–697
(1996
).61.
P. A.
Thompson
, V.
Muñoz
, G. S.
Jas
, E. R.
Henry
, W. A.
Eaton
, and J.
Hofrichter
, “The helix-coil kinetics of a heteropeptide
,” J. Phys. Chem. B.
104
, 378
–389
(2000
).62.
G.
Hummer
, A.
García
, and S.
Garde
, “Conformational diffusion and helix formation kinetics
,” Phys. Rev. Lett.
85
, 2637
–2640
(2000
).63.
G.
Hummer
, A. E.
García
, and S.
Garde
, “Helix nucleation kinetics from molecular simulations in explicit solvent
,” Proteins: Struct., Funct., Genet.
42
, 77
–84
(2001
).64.
G. S.
Jas
, C. R.
Middaugh
, and K.
Kuczera
, “Non-exponential kinetics and a complete folding pathway of an α-helical heteropeptide: Direct observation and comprehensive molecular dynamics
,” J. Phys. Chem. B.
118
, 639
–647
(2014
).65.
U. H. E.
Hansmann
and Y.
Okamoto
, “Finite-size scaling of helix-coil transitions in poly-alanine studied by multicanonical simulations
,” J. Chem. Phys.
110
, 1267
(1999
);U. H. E.
Hansmann
and Y.
Okamoto
, e-print arXiv:9810358 [cond-mat].66.
A.
Hazel
, C.
Chipot
, and J. C.
Gumbart
, “Thermodynamics of deca-alanine folding in water
,” J. Chem. Theory Comput.
10
, 2836
–2844
(2014
).67.
A. D. J.
Mackerell
, “Empirical force fields for biological macromolecules: Overview and issues
,” J. Comput. Chem.
25
, 1584
–1604
(2004
).68.
J.
Vymetal
and J.
Vondrasek
, “Critical assessment of current force fields. Short peptide test case
,” J. Chem. Theory Comput.
9
, 441
–451
(2013
).69.
T.
Schlesier
and G.
Diezemann
, “Performance of different force fields in force probe simulations
,” J. Phys. Chem. B
117
, 1862
–1871
(2013
).70.
B.
Lindner
, Z.
Yi
, J.-H.
Prinz
, J. C.
Smith
, and F.
Noé
, “Dynamic neutron scattering from conformational dynamics. I. Theory and Markov models
,” J. Chem. Phys.
139
, 175101
(2013
).71.
Z.
Yi
, B.
Lindner
, J.-H.
Prinz
, F.
Noé
, and J. C.
Smith
, “Dynamic neutron scattering from conformational dynamics. II. Application using molecular dynamics simulation and Markov modeling
,” J. Chem. Phys.
139
, 175102
(2013
).72.
W.
Zhuang
, R. Z.
Cui
, D.-A.
Silva
, and X.
Huang
, “Simulating the T-jump-triggered unfolding dynamics of trpzip2 peptide and its time-resolved IR and two-dimensional IR signals using the Markov state model approach
,” J. Phys. Chem. B
115
, 5415
–5424
(2011
).73.
J.
Xia
, N.-j.
Deng
, and R. M.
Levy
, “NMR relaxation in proteins with fast internal motions and slow conformational exchange: Model-free framework and Markov state simulations
,” J. Phys. Chem. B
117
, 6625
–6634
(2013
).74.
J.-H.
Prinz
, J. D.
Chodera
, V. S.
Pande
, W. C.
Swope
, J. C.
Smith
, and F.
Noé
, “Optimal use of data in parallel tempering simulations for the construction of discrete-state Markov models of biomolecular dynamics
,” J. Chem. Phys.
134
, 244108
(2011
).75.
J. D.
Chodera
, W. C.
Swope
, F.
Noé
, J.-H.
Prinz
, M. R.
Shirts
, and V. S.
Pande
, “Dynamical reweighting: Improved estimates of dynamical properties from simulations at multiple temperatures
,” J. Chem. Phys.
134
, 244107
(2011
).76.
M.
Di Pierro
, M. L.
Mugnai
, and R.
Elber
, “Optimizing potentials for a liquid mixture: A new force field for a tert-butanol and water solution
,” J. Chem. Phys. B
119
, 836
(2014
).77.
M.
Pirchi
, G.
Ziv
, I.
Riven
, S. S.
Cohen
, N.
Zohar
, Y.
Barak
, and G.
Haran
, “Single-molecule fluorescence spectroscopy maps the folding landscape of a large protein
,” Nat. Commun.
2
, 493
(2011
).78.
B. G.
Keller
, A.
Kobitski
, A.
Jäschke
, G. U.
Nienhaus
, and F.
Noé
, “Complex RNA folding kinetics revealed by single-molecule FRET and hidden Markov models
,” J. Am. Chem. Soc.
136
, 4534
–4543
(2014
).79.
J.
Stigler
, F.
Ziegler
, A.
Gieseke
, J. C. M.
Gebhardt
, and M.
Rief
, “The complex folding network of single calmodulin molecules
,” Science
334
, 512
–516
(2011
).80.
F.
Noé
, H.
Wu
, J.-H.
Prinz
, and N.
Plattner
, “Projected and hidden Markov models for calculating kinetics and metastable states of complex molecules
,” J. Chem. Phys.
139
, 184114
(2013
).© 2015 AIP Publishing LLC.
2015
AIP Publishing LLC
You do not currently have access to this content.
