Skip to main content
Log in

Validation of the 53A6 GROMOS force field

  • Article
  • Published:
European Biophysics Journal Aims and scope Submit manuscript

Abstract

The quality of biomolecular dynamics simulations relies critically on the force field that is used to describe the interactions between particles in the system. Force fields, which are generally parameterized using experimental data on small molecules, can only prove themselves in realistic simulations of relevant biomolecular systems. In this work, we begin the validation of the new 53A6 GROMOS parameter set by examining three test cases. Simulations of the well-studied 129 residue protein hen egg-white lysozyme, of the DNA dodecamer d(CGCGAATTCGCG)2, and a proteinogenic β3-dodecapeptide were performed and analysed. It was found that the new parameter set performs as well as the previous parameter sets in terms of protein (45A3) and DNA (45A4) stability and that it is better at describing the folding–unfolding balance of the peptide. The latter is a property that is directly associated with the free enthalpy of hydration, to which the 53A6 parameter set was parameterized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Altona C, Sundaralingam M (1972) Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation. J Am Chem Soc 94:8205–8212

    Google Scholar 

  • Altona C, Geise HJ, Romers C (1968) Conformation of non-aromatic ring compounds-XXV. Geometry and conformation of ring D in some steroids from X-ray structure determinations. Tetrahedron 24:13–32

    Google Scholar 

  • Antes I, Thiel W, Gunsteren WF van (2002) Molecular dynamics simulations of photoactive yellow protein (PYP) in three states of its photocycle: a comparison with X-ray and NMR data and analysis of the effects of Glu46 deprotonation and mutation. Eur Biophys J 31:504–520

    Google Scholar 

  • Arthanari H, McConnell KJ, Beger R, Young MA, Beveridge DL, Bolton PH (2003) Assessment of the molecular dynamics structure of DNA in solution based on calculated and observed NMR NOESY volumes and dihedral angles from scalar coupling constants. Biopolymers 68:3–15

    Google Scholar 

  • Artymiuk PJ, Blake CCF, Rice DW, Wilson KS (1982) The structures of the monoclinic and orthorhombic forms of hen egg-white lysozyme at 6 Å resolution. Acta Cryst B38:778–783

    Google Scholar 

  • Bakowies D, Gunsteren WF van (2002) Simulations of apo- and holo-fatty acid binding protein: structure and dynamics of protein, ligand and internal water. J Mol Biol 315:713–736

    Google Scholar 

  • Berendsen HJC, Postma JPM, Gunsteren WF van, Hermans J (1981) Interaction models for water in relation to protein hydration. In: Pullman B (ed) Intermolecular forces. Reidel, Dordrecht, pp 331–342

    Google Scholar 

  • Berendsen HJC, Postma JPM, Gunsteren WF van, DiNola A, Haak JR (1984) Molecular-dynamics with coupling to an external bath. J Chem Phys 81:3684–3690

    CAS  Google Scholar 

  • Bonvin AMJJ, Sunnerhagen M, Otting G, Gunsteren WF van (1998) Water molecules in DNA recognition II: a molecular dynamics view of the structure and hydration of the Trp operator. J Mol Biol 282:859–873

    Google Scholar 

  • Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) CHARMM - A program for macromolecular energy, minimization and dynamics calculations. J Comput Chem 4:187–217

    Article  Google Scholar 

  • Buck M, Boyd DB, Redfield C, MacKenzie DA, Jeenes DJ, Archer DB, Dobson CM (1995) Structural determinants of protein dynamics: analysis of 15 N NMR relaxation measurements for main-chain and side-chain nuclei of hen egg white lysozyme. Biochemistry 34:4041–4055

    Google Scholar 

  • Carter D, He J, Ruble JR, Wright B (1997) The structure of the orthorhombic form of hen egg-white lysozyme at 1.5 Å resolution. Protein Data Bank, entry 1AKI

  • Chandrasekhar I, Gunsteren WF van (2002) A comparison of the potential energy parameters of aliphatic alkanes: molecular dynamics simulations of triacylglycerols in the alpha phase. Eur Biophys J 31:89–101

    Google Scholar 

  • Chandrasekhar I, Kastenholz MA, Lins RD, Oostenbrink C, Schuler LD, Tieleman DP, Gunsteren WF van (2003) A consistent potential energy parameter set for lipids: dipalmitoylphosphatidylcholine as a benchmark of the GROMOS96 45A3 force field. Eur Biophys J 32:67–77

    Google Scholar 

  • Cheatham III TE, Kollman PA (2000) Molecular dynamics simulation of nucleic acids. Annu Rev Phys Chem 51:435–471

    Google Scholar 

  • Cheatham III TE, Young MA (2000) Molecular dynamics simulation of nucleic acids: successes, limitations, and promise. Biopolymers 56:232–256

    Google Scholar 

  • Constantine KL, Madrid M, Bányai L, Trexler M, Patthy L, Llinás M (1992) Refined solution structure and ligand-binding properties of PDC-109 domain b. A collagen-binding type II domain. J Mol Biol 223:281–298

    Google Scholar 

  • Cornell WD, Cieplak P, Bayly CI, Gould IR, Mertz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) A second generation force field for the simulation of proteins, nucleic acids and organic molecules. J Am Chem Soc 117:5179–5197

    CAS  Google Scholar 

  • Czechtizky W, Daura X, Vasella A, Gunsteren WF van (2001) Oligonucleotide analogues with a nucleobase-including backbone. Part 7: molecular dynamics simulation of a DNA duplex containing a 2′-deoxyadenosine 8-(hydroxymethyl)-derived nucleotide. Helv Chim Acta 84:2132–2145

    Google Scholar 

  • Daura X, Gunsteren WF van, Rigo D, Jaun B, Seebach D (1997) Studying the stability of a helical ß-heptapeptide by molecular dynamics simulations. Chem Eur J 3:1410–1417

    Google Scholar 

  • Daura X, Mark AE, Gunsteren WF van (1998) Parametrization of aliphatic CHn united atoms of GROMOS96 force field. J Comput Chem 19:535–547

    Google Scholar 

  • Daura X, Gademann K, Jaun B, Seebach D, Gunsteren WF van, Mark AE (1999a) Peptide folding: when simulation meets experiment. Angew Chem Int Ed 38:236–240

    Google Scholar 

  • Daura X, Gunsteren WF van, Mark AE (1999b) Folding-unfolding thermodynamics of a β-heptapeptide from equilibrium simulations. Proteins 34:269–280

    Google Scholar 

  • Daura X, Glättli A, Gee P, Peter C, Gunsteren WF van (2002) The unfolded state of peptides. Adv Protein Chem 62:341–360

    Google Scholar 

  • Dickerson RE, Drew HR (1981) Structure of a B-DNA dodecamer. 2. Influence of base sequence on helix structure. J Mol Biol 149:761–786

    Google Scholar 

  • Drew HR, Dickerson RE (1981) Structure of a B-DNA dodecamer. 3. Geometry of hydration. J Mol Biol 151:535–556

    Google Scholar 

  • Drew HR, Wing RM, Takano T, Broka C, Tanaka S, Itakura K, Dickerson RE (1981) Structure of a B-DNA dodecamer—conformation and dynamics. Proc Natl Acad Sci USA 78:2179–2183

    Google Scholar 

  • Etezady-Esfarjani T, Hilty C, Wüthrich K, Rueping M, Schreiber J, Seebach D (2002) NMR-structural investigations of a β3-dodecapeptide with proteinogenic side chains in methanol and in aqueous solutions. Helv Chim Acta 85:1197–1209

    Google Scholar 

  • Fan H, Mark AE (2003) Relative stability of protein structures determined by X-ray crystallography or NMR spectroscopy: a molecular dynamics simulation study. Proteins 53:111–120

    Google Scholar 

  • Fan H, Mark AE (2004) Refinement of homology-based protein structures by molecular dynamics simulation techniques. Protein Sci 13:211–220

    Google Scholar 

  • Fioroni M, Burger K, Mark AE, Roccatano D (2000) A new 2,2,2-trifluoroethanol model for molecular dynamics simulations. J Phys Chem B 104:12347–12354

    Google Scholar 

  • Fletcher CM, Jones DNM, Diamond R, Neuhaus D (1996) Treatment of NOE constraints involving equivalent or nonstereoassigned protons in calculations of biomacromolecular structures. J Biomol NMR 8:292–310

    Google Scholar 

  • Geerke DP, Oostenbrink C, Vegt NFA van der, Gunsteren WF van (2004) An effective force field for molecular dynamics simulations of dimethyl sulfoxide and dimethyl sulfoxide-water mixtures. J Phys Chem B 108:1436–1445

    Google Scholar 

  • Glättli A, Daura X, Seebach D, Gunsteren WF van (2002a) Can one derive the conformational preference of a beta-peptide from its CD spectrum. J Am Chem Soc 124:12972–12184

    Google Scholar 

  • Glättli A, Daura X, Gunsteren WF van (2002b) Derivation of an improved simple point charge model for liquid water: SPC/A and SPC/L. J Chem Phys 116:9811–9828

    Google Scholar 

  • Gunsteren WF van, Berendsen HJC (1987) Groningen molecular simulation (GROMOS) library manual. Biomos, Groningen

    Google Scholar 

  • Gunsteren WF van, Mark AE (1998) Validation of molecular dynamics simulation. J Chem Phys 108:6109–6116

    Google Scholar 

  • Gunsteren WF van, Billeter SR, Eising AA, Hünenberger PH, Krüger P, Mark AE, Scott WRP, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide. Vdf Hochschulverlag AG an der ETH Zürich, Zürich

    Google Scholar 

  • Gunsteren WF van, Daura X, Mark AE (1998) GROMOS force field. In: von Ragué Schleyer P (ed) Encyclopedia of computational chemistry, vol 2. Wiley, New York, pp 1211–1216

  • Gunsteren WF van, Bürgi R, Peter C, Daura X (2001) The key to solving the protein-folding problem lies in an accurate description of the denatured state. Angew Chem Int Ed 40:351–355

    Google Scholar 

  • Hansson T, Marelius J, Åqvist J (1998) Ligand binding affinity prediction by linear interaction energy methods. J Comput-Aid Mol Des 12:27–35

    Google Scholar 

  • Heinz TN, Gunsteren WF van, Hünenberger PH (2001) Comparison of four methods to compute the dielectric permittivity of liquids from molecular dynamics simulations. J Chem Phys 115:1125–1136

    Google Scholar 

  • Hermans J, Berendsen HJC, Gunsteren WF van, Postma JPM (1984) A consistent empirical potential for water-protein interactions. Biopolymers 23:1513–1518

    Google Scholar 

  • Jorgensen WL, Tirado-Rives J (1988) The OPLS potential functions for proteins—energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc 110:1657–1666

    Google Scholar 

  • Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236

    Article  CAS  Google Scholar 

  • Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637

    CAS  PubMed  Google Scholar 

  • Lins RD, Hünenberger PH (2005) A new GROMOS parameter set for hexapyranose-based carbohydrates. J Comput Chem (submitted)

  • Lu X-J, Olson WK (2003) 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res 31:5108–5121

    Google Scholar 

  • MacCallum JL, Tieleman DP (2003) Calculation of the water-cyclohexane transfer free energies of neutral amino acid side-chain analogs using the OPLS all-atom force field. J Comput Chem 24:1930–1935

    Google Scholar 

  • MacKerell Jr. AD, Wiórkiewicz-Kuczera J, Karplus M (1995) An all-atom empirical energy function for the simulation of nucleic-acids. J Am Chem Soc 117:11946–11975

    Google Scholar 

  • MacKerell Jr AD, Bashford D, Bellot M, Dunbrack Jr. RL, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph-McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher III WE, Roux B, Schlenkrich M, Smith JC, Stote, R., Straub J, Watanabe M, Wiórkiewicz-Kuczera J, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586–3616

    Article  CAS  Google Scholar 

  • Marelius J, Hansson T, Åqvist J (1998) Calculation of ligand binding free energies from molecular dynamics simulations. Int J Quantum Chem 69:77–88

    Google Scholar 

  • Olson W, Bansal M, Burley SK, Dickerson RE, Gerstein M, Harvey SC, Heinemann U, Lu X-J, Neidle S, Shakked Z, Sklenar H, Suzuki M, Tung C-S, Westhof E, Wolberger C, Berman HM (2001) A standard reference frame for the description of nucleic acid base-pair geometry. J Mol Biol 313:229–237

    Google Scholar 

  • Oostenbrink C, Gunsteren WF van (2004) Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation. Proteins 54:237–246

    Google Scholar 

  • Oostenbrink BC, Pitera JW, Van Lipzig MMH, Meerman JHN, Gunsteren WF van (2000) Simulations of the estrogen receptor ligand-binding domain: affinity of natural ligands and xenoestrogens. J Med Chem 43:4594–4605

    Google Scholar 

  • Oostenbrink C, Villa A, Mark AE, Gunsteren WF van (2004) 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

    Google Scholar 

  • Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham III TE, DeBolt S, Ferguson D, Seibel G, Kollman PA (1995) AMBER, a package of computer-programs for applying molecular mechanics, normal-mode analysis, molecular-dynamics and free-energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Comm 91:1–41

    Google Scholar 

  • Peter C, Daura X, Gunsteren WF van (2000) Peptides of aminoxy acids: a molecular dynamics simulation of conformational equilibria under various conditions. J Am Chem Soc 122:7461–7466

    Google Scholar 

  • Ryckaert J-P, Ciccotti G, Berendsen HJC (1977) Numerical integration of cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    CAS  Google Scholar 

  • Schuler LD, Gunsteren WF van (2000) On the choice of dihedral angle potential energy functions for n-alkanes. Mol Simulat 25:301–319

    Google Scholar 

  • Schuler LD, Daura X, Gunsteren WF van (2001) An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase. J Comput Chem 22:1205–1218

    Google Scholar 

  • Schwalbe H, Grimshaw SB, Spencer A, Buck M, Boyd J, Dobson CM, Redfield C, Smith LJ (2001) A refined solution structure of hen lysozyme determined using residual dipolar coupling data. Protein Sci 10:677–688

    Google Scholar 

  • Scott WRP, Hünenberger PH, Tironi IG, Mark AE, Billeter SR, Fennen J, Torda AE, Huber P, Krüger P, Gunsteren WF van (1999) The GROMOS biomolecular simulation program package. J Phys Chem A 103:3596–3607

    Google Scholar 

  • Shirts MR, Pitera JW, Swope WC, Pande VS (2003) Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins. J Chem Phys 119:5740–5760

    Google Scholar 

  • Shui X, McFail-Isom L, Hu GG, Dean Williams L (1998) The B-DNA dodecamer at high resolution reveals a spine of water on sodium. Biochemistry 37:8341–8355

    Google Scholar 

  • Smith LJ, Sutcliffe MJ, Redfield C, Dobson CM (1991) Analysis of ϕ and χ1 torsion angles for hen lysozyme in solution from 1 H NMR spin-spin coupling constants. Biochemistry 30:986–996

    Google Scholar 

  • Smith LJ, Sutcliffe MJ, Redfield C, Dobson CM (1993) Structure of hen lysozyme in solution. J Mol Biol 229:930–944

    Google Scholar 

  • Smith LJ, Mark AE, Dobson CM, Gunsteren WF van (1995) Comparison of MD simulations and NMR experiments for hen lysozyme: analysis of local fluctuations, cooperative motions and global changes. Biochemistry 34:10918–10931

    Google Scholar 

  • Smith LJ, Dobson CM, Gunsteren WF van (1996) Side-chain conformational disorder in a molten globule: molecular dynamics simulations of the A-state of human alpha-lactalbumin. J Mol Biol 286:1567–1580

    Google Scholar 

  • Smith LJ, Dobson CM, Gunsteren WF van (1999) Molecular dynamics simulations of human alpha-lactalbumin. Changes of the structural and dynamical properties of the protein at low pH. Proteins 36:77–86

    Google Scholar 

  • Smith LJ, Berendsen HJC, Gunsteren WF van (2004) Computer simulation of urea-water mixtures: A test of force field parameters for use in biomolecular simulation. J Phys Chem A 108:1065–1071

    Google Scholar 

  • Soares T, Daura X, Oostenbrink C, Smith LJ, van Gunsteren WF (2004) Validation of the GROMOS force-field parameter set 45A3 against nuclear magnetic resonance data of Hen Egg Lysozyme. J Biomol NMR 30:407–422

    Google Scholar 

  • Soares TA, Hünenberger PH, Kastenholz MA, Kräutter V, Lenz T, Lins RD,Oostenbrink C, van Gunsteren WF (2005) An improved nucleic-acid parameter set for the GROMOS force field. J Comput Chem (in press)

  • Stocker U, Gunsteren WF van (2000) Molecular dynamics simulation of hen egg white lysozyme: a test of the GROMOS96 force field against nuclear magnetic resonance data. Proteins 40:145–153

    Google Scholar 

  • Stocker U, Spiegel K, Gunsteren WF van (2000) On the similarity of properties in solution or in the crystalline state: a molecular dynamics study of hen lysozyme. J Biomol NMR 18:1–12

    Google Scholar 

  • Talhout R, Villa A, Mark AE, Engberts JBFN (2003) Understanding binding affinity: a combined isothermal titration calorimetry/molecular dynamics study of the binding of a series of hydrophobically modified benzamidinium chloride inhibitors to trypsin. J Am Chem Soc 125:10570–10579

    Google Scholar 

  • Tironi IG, Sperb R, Smith PE, Gunsteren WF van (1995) A generalized reaction field method for molecular-dynamics simulations. J Chem Phys 102:5451–5459

    Google Scholar 

  • Tjandra N, Tate S, Ono A, Kainosho M, Bax A (2000) The NMR structure of a DNA dodecamer in an aqueous dilute crystalline phase. J Am Chem Soc 122:6190–6200

    Google Scholar 

  • Tropp J (1980) Dipolar relaxation and nuclear Overhauser effects in nonrigid molecules: the effect of fluctuating internuclear distances. J Chem Phys 72:6035–6043

    Google Scholar 

  • Vaney MC, Maignan S, RiesKautt M, Ducruix A (1996) High-resolution structure (1.33 angstrom) of a HEW lysozyme tetragonal crystal grown in the APCF apparatus. Data and structural comparison with a crystal grown under microgravity from SpaceHab-01 mission. Acta Cryst D52:505–517

    Google Scholar 

  • Villa A, Mark AE (2002) Calculation of the free energy of solvation for neutral analogs of amino acid side chains. J Comput Chem 23:548–553

    Google Scholar 

  • Walser R, Mark AE, Gunsteren WF van, Lauterbach M, Wipff G (2000) The effect of force-field parameters on properties of liquids: parametrization of a simple three-site model for methanol. J Chem Phys 112:10450–10459

    Google Scholar 

  • Weiner PK, Kollman PA (1981) AMBER—assisted model-building with energy refinement—a general program for modeling molecules and their interactions. J Comput Chem 2:287–303

    Google Scholar 

  • Wüthrich K, Billeter M, Braun W (1983) Pseudo-structures for the 20 common amino-acids for use in studies of protein conformations by measurements of intramolecular proton–proton distance constraints with nuclear magnetic resonance. J Mol Biol 169:949–961

    Google Scholar 

  • Young MA, Jayaram B, Beveridge DL (1997) Intrusion of counterions into the spine of hydration in the minor groove of B-DNA: fractional occupancy of electronegative pockets. J Am Chem Soc 119:59–69

    Google Scholar 

Download references

Acknowledgments

Professor Dr. K. Wüthrich is gratefully acknowledged for making the experimental data on the β3-dodecamer available. We also thank Lorna Smith for helpful discussions on the NOE analysis. Financial support by the National Center of Competence in Research (NCCR) in Structural Biology of the Swiss National Science Foundation (SNSF) is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wilfred F. van Gunsteren.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oostenbrink, C., Soares, T.A., van der Vegt, N.F.A. et al. Validation of the 53A6 GROMOS force field. Eur Biophys J 34, 273–284 (2005). https://doi.org/10.1007/s00249-004-0448-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00249-004-0448-6

Keywords

Navigation