We present a systematic study of the long-timescale dynamics of the Drew-Dickerson dodecamer (DDD: d(CGCGAATTGCGC)2) a prototypical B-DNA duplex. Using our newly parameterized PARMBSC1 force field, we describe the conformational landscape of DDD in a variety of ionic environments from minimal salt to 2 M Na(+)Cl(-) or K(+)Cl(-) The sensitivity of the simulations to the use of different solvent and ion models is analyzed in detail using multi-microsecond simulations. Finally, an extended (10 μs) simulation is used to characterize slow and infrequent conformational changes in DDD, leading to the identification of previously uncharacterized conformational states of this duplex which can explain biologically relevant conformational transitions. With a total of more than 43 μs of unrestrained molecular dynamics simulation, this study is the most extensive investigation of the dynamics of the most prototypical DNA duplex.

Bases Moléculaires et Structurales des Systèmes Infectieux Université Lyon 1 CNRS UMR 5086 IBCP 7 Passage du Vercors Lyon 69367 France

Department of Biochemistry and Molecular Biology University of Barcelona 08028 Barcelona Spain

Institute for Research in Biomedicine Norwich Research Park Norwich NR4 7TJ UK

Institute for Research in Biomedicine The Barcelona Institute of Science and Technology Baldiri Reixac 10 12 08028 Barcelona Spain Joint BSC IRB Research Program in Computational Biology Baldiri Reixac 10 12 08028 Barcelona Spain

Institute for Research in Biomedicine The Barcelona Institute of Science and Technology Baldiri Reixac 10 12 08028 Barcelona Spain Joint BSC IRB Research Program in Computational Biology Baldiri Reixac 10 12 08028 Barcelona Spain Department of Biochemistry and Molecular Biology University of Barcelona 08028 Barcelona Spain

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo nám 2 166 10 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo nám 2 166 10 Prague Czech Republic Laboratory of Informatics and Chemistry University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

See more in PubMed

Hud N.V. Biomolecular Sciences. Cambridge: The Royal Society of Chemistry; 2008. Nucleic Acid-Metal Ion Interactions.

Geggier S., Vologodskii A. Sequence dependence of DNA bending rigidity. Proc. Natl. Acad. Sci. U.S.A. 2010;107:15421–15426. PubMed PMC

Huguet J.M., Bizarro C. V, Forns N., Smith S.B., Bustamante C., Ritort F. Single-molecule derivation of salt dependent base-pair free energies in DNA. Proc. Natl. Acad. Sci. U.S.A. 2010;107:15431–15436. PubMed PMC

Heng J.B., Aksimentiev A., Ho C., Marks P., Grinkova Y.V., Sligar S., Schulten K., Timp G. The electromechanics of DNA in a synthetic nanopore. Biophys. J. 2006;90:1098–1106. PubMed PMC

Strick T.R., Dessinges M.-N., Charvin G., Dekker N.H., Allemand J.-F., Bensimon D., Croquette V. Stretching of macromolecules and proteins. Reports Prog. Phys. 2003;66:1–45.

Pérez A., Lankas F., Luque F.J., Orozco M. Towards a molecular dynamics consensus view of B-DNA flexibility. Nucleic Acids Res. 2008;36:2379–2394. PubMed PMC

Dršata T., Pérez A., Orozco M., Morozov A. V, Sponer J., Lankaš F. Structure, stiffness and substates of the dickerson-drew dodecamer. J. Chem. Theory Comput. 2013;9:707–721. PubMed PMC

Pasi M., Maddocks J.H., Beveridge D., Bishop T.C., Case D.A., Cheatham T., Dans P.D., Jayaram B., Lankas F., Laughton C., et al. μABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA. Nucleic Acids Res. 2014;42:12272–12283. PubMed PMC

Lankas F., Sponer J., Hobza P., Langowski J. Sequence-dependent elastic properties of DNA. J. Mol. Biol. 2000;299:695–709. PubMed

Dršata T., Lankaš F. Multiscale modelling of DNA mechanics. J. Phys. Condens. Matter. 2015;27:323102. PubMed

Pérez A., Luque F.J., Orozco M. Frontiers in molecular dynamics simulations of DNA. Acc. Chem. Res. 2012;45:196–205. PubMed

Arcella A., Dreyer J., Ippoliti E., Ivani I., Portella G., Gabelica V., Carloni P., Orozco M. Structure and dynamics of oligonucleotides in the gas phase. Angew. Chem. Int. Ed. Engl. 2015;54:467–471. PubMed

Portella G., Germann M.W., Hud N.V., Orozco M. MD and NMR analyses of choline and TMA binding to duplex DNA: on the origins of aberrant sequence-dependent stability by alkyl cations in aqueous and water-free solvents. J. Am. Chem. Soc. 2014;136:3075–3086. PubMed

Arcella A., Portella G., Collepardo-Guevara R., Chakraborty D., Wales D.J., Orozco M. Structure and properties of DNA in apolar solvents. J. Phys. Chem. B. 2014;118:8540–8548. PubMed PMC

Dans P.D., Walther J., Gómez H., Orozco M. Multiscale simulation of DNA. Curr. Opin. Struct. Biol. 2016;37:29–45. PubMed

Sponer J., Cang X., Cheatham T.E. Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures. Methods. 2012;57:25–39. PubMed PMC

Sim A.Y.L., Minary P., Levitt M. Modeling nucleic acids. Curr. Opin. Struct. Biol. 2012;22:273–278. PubMed PMC

Várnai P., Zakrzewska K. DNA and its counterions: a molecular dynamics study. Nucleic Acids Res. 2004;32:4269–4280. PubMed PMC

Pérez A., Marchán I., Svozil D., Sponer J., Cheatham T.E., Laughton C.A., Orozco M. Refinement of the AMBER force field for nucleic acids: improving the description of alpha/gamma conformers. Biophys. J. 2007;92:3817–3829. PubMed PMC

Ivani I., Dans P.D., Noy A., Pérez A., Faustino I., Hospital A., Walther J., Andrio P., Goñi R., Balaceanu A., et al. Parmbsc1: a refined force field for DNA simulations. Nat. Methods. 2015;13:55–58. PubMed PMC

Drew H.R., Wing R.M., Takano T., Broka C., Tanaka S., Itakura K., Dickerson R.E. Structure of a B-DNA dodecamer: conformation and dynamics. Proc. Natl. Acad. Sci. U.S.A. 1981;78:2179–2183. PubMed PMC

Pérez A., Luque F.J., Orozco M. Dynamics of B-DNA on the microsecond time scale. J. Am. Chem. Soc. 2007;129:14739–14745. PubMed

Trieb M., Rauch C., Wellenzohn B., Wibowo F., Loerting T., Liedl K.R. Dynamics of DNA: B I and B II Phosphate Backbone Transitions. J. Phys. Chem. B. 2004;108:2470–2476.

Arnott S., Hukins D.W. Optimised parameters for A-DNA and B-DNA. Biochem. Biophys. Res. Commun. 1972;47:1504–1509. PubMed

Howerton S., Sines C., VanDerveer D., Williams L.D. Locating monovalent cations in the grooves of B-DNA. Biochemistry. 2001;40:10023–10031. PubMed

Smith D.E., Dang L.X. Computer simulations of NaCl association in polarizable water. J. Chem. Phys. 1994;100:3757–3766.

Joung I.S., Cheatham T.E. Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J. Phys. Chem. B. 2008;112:9020–9041. PubMed PMC

Jensen K.P., Jorgensen W.L. Halide, ammonium, and alkali metal ion parameters for modeling aqueous solutions. J. Chem. Theory Comput. 2006;2:1499–1509. PubMed

Beglov D., Roux B. Finite representation of an infinite bulk system: Solvent boundary potential for computer simulations. J. Chem. Phys. 1994;100:9050–9063.

Shields G.C., Laughton C.A., Orozco M. Molecular dynamics simulations of the d(T·A·T) triple helix. J. Am. Chem. Soc. 1997;119:7463–7469.

Berendsen H.J.C., Postma J.P.M., van Gunsteren W.F., DiNola A., Haak J.R. Molecular dynamics with coupling to an external bath. 1984;81:3684–3690.

Mor A., Ziv G., Levy Y. Simulations of proteins with inhomogeneous degrees of freedom: The effect of thermostats. J. Comput. Chem. 2008;29:1992–1998. PubMed

Nosé S., Klein M.L. Constant pressure molecular dynamics for molecular systems. Mol. Phys. 2006;50:1055–1076.

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

Darden T., York D., Pedersen L. Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J. Chem. Phys. 1993;98:10089–10092.

Salomon-Ferrer R., Götz A.W., Poole D., Le Grand S., Walker R.C. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 2013;9:3878–3888. PubMed

Case D.A., Babin V., Berryman J.T., Betz R.M., Cai Q., Cerutti D.S., Cheatham T.E. III, Darden T.A., Duke R.E., Gohlke H., et al. AMBER. San Francisco: University of California; 2014.

Roe D.R., Cheatham T.E. PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput. 2013;9:3084–3095. PubMed

Hospital A., Faustino I., Collepardo-Guevara R., González C., Gelpí J.L., Orozco M. NAFlex: a web server for the study of nucleic acid flexibility. Nucleic Acids Res. 2013;41:W47–W55. PubMed PMC

Lavery R., Moakher M., Maddocks J.H., Petkeviciute D., Zakrzewska K. Conformational analysis of nucleic acids revisited: Curves+ Nucleic Acids Res. 2009;37:5917–5929. PubMed PMC

Zuo X., Cui G., Merz K.M., Zhang L., Lewis F.D., Tiede D.M. X-ray diffraction “fingerprinting” of DNA structure in solution for quantitative evaluation of molecular dynamics simulation. Proc. Natl. Acad. Sci. U.S.A. 2006;103:3534–3539. PubMed PMC

Park S., Bardhan J.P., Roux B., Makowski L. Simulated x-ray scattering of protein solutions using explicit-solvent models. J. Chem. Phys. 2009;130:134114. PubMed PMC

Nguyen H.T., Pabit S.A., Meisburger S.P., Pollack L., Case D.A. Accurate small and wide angle x-ray scattering profiles from atomic models of proteins and nucleic acids. J. Chem. Phys. 2014;141:22D508. PubMed PMC

Zuo X., Tiede D.M. Resolving conflicting crystallographic and NMR models for solution-state DNA with solution X-ray diffraction. J. Am. Chem. Soc. 2005;127:16–17. PubMed

Lavery R., Maddocks J.H., Pasi M., Zakrzewska K. Analyzing ion distributions around DNA. Nucleic Acids Res. 2014;42:8138–8149. PubMed PMC

Dans P.D., Faustino I., Battistini F., Zakrzewska K., Lavery R., Orozco M. Unraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNA. Nucleic Acids Res. 2014;42:11304–11320. PubMed PMC

Pasi M., Maddocks J.H., Lavery R. Analyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamics. Nucleic Acids Res. 2015;43:2412–2423. PubMed PMC

Schlitter J. Estimation of absolute and relative entropies of macromolecules using the covariance matrix. Chem. Phys. Lett. 1993;215:617–621.

Andricioaei I., Karplus M. On the calculation of entropy from covariance matrices of the atomic fluctuations. J. Chem. Phys. 2001;115:6289–6292.

Hess B. Similarities between principal components of protein dynamics and random diffusion. Phys. Rev. E. Stat. Phys. Plasmas. Fluids. Relat. Interdiscip. Topics. 2000;62:8438–8448. PubMed

Pérez A., Blas J.R., Rueda M., López-Bes J.M., de la Cruz X., Orozco M. Exploring the essential dynamics of B-DNA. J. Chem. Theory Comput. 2005;1:790–800. PubMed

Orozco M., Pérez A., Noy A., Luque F.J. Theoretical methods for the simulation of nucleic acids. Chem. Soc. Rev. 2003;32:350–364. PubMed

Noy A., Golestanian R. Length Scale Dependence of DNA Mechanical Properties. Phys. Rev. Lett. 2012;109:228101. PubMed

Zheng G., Czapla L., Srinivasan A.R., Olson W.K. How stiff is DNA? Phys. Chem. Chem. Phys. 2010;12:1399–1406. PubMed PMC

Mecklin C.J. Shapiro-Wilk Test for Normality. In: Salkind NJ, Rasmussen K, editors. Encyclopedia of Measurement and Statistics. Thousand Oaks: SAGE Publications, Inc; 2007. pp. 884–887.

R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013.

Wickham H. ggplot2. NY: Springer; 2009.

Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J. Mol. Graph. 1996;14:33–38. PubMed

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera–a visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. PubMed

Savelyev A., MacKerell A.D. Differential impact of the monovalent ions Li(+), Na(+), K(+), and Rb(+) on DNA conformational properties. J. Phys. Chem. Lett. 2015;6:212–216. PubMed PMC

Jorgensen W.L., Chandrasekhar J., Madura J.D., Impey R.W., Klein M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983;79:926–935.

Berendsen H.J.C., Grigera J.R., Straatsma T.P. The missing term in effective pair potentials. J. Phys. Chem. 1987;91:6269–6271.

Noy A., Soteras I., Luque F.J., Orozco M. The impact of monovalent ion force field model in nucleic acids simulations. Phys. Chem. Chem. Phys. 2009;11:10596–10607. PubMed

Pérez A., Luque F.J., Orozco M. Frontiers in molecular dynamics simulations of DNA. Acc. Chem. Res. 2012;45:196–205. PubMed

Savelyev A., MacKerell A.D. Differential impact of the monovalent ions Li+, Na+, K+, and Rb+ on DNA conformational properties. J. Phys. Chem. Lett. 2015;6:212–216. PubMed PMC

Levitt M. The birth of computational structural biology. Nat. Struct. Biol. 2001;8:392–393. PubMed

Bixon M., Lifson S. Potential functions and conformations in cycloalkanes. Tetrahedron. 1967;23:769–784.

Mazur A.K., Maaloum M. Atomic force microscopy study of DNA flexibility on short length scales: smooth bending versus kinking. Nucleic Acids Res. 2014;42:14006–14012. PubMed PMC

Noy A., Golestanian R. The chirality of DNA: elasticity cross-terms at base-pair level including A-tracts and the influence of ionic strength. J. Phys. Chem. B. 2010;114:8022–8031. PubMed

de Leeuw S.W., Perram J.W., Smith E.R. Simulation of electrostatic systems in periodic boundary conditions. I. Lattice sums and dielectric constants. Proc. R. Soc. A Math. Phys. Eng. Sci. 1980;373:27–56.

Sagui C., Darden T.A. Molecular dynamics simulations of biomolecules: long-range electrostatic effects. Annu. Rev. Biophys. Biomol. Struct. 1999;28:155–179. PubMed

Shui X., McFail-Isom L., Hu G.G., Williams L.D. The B-DNA dodecamer at high resolution reveals a spine of water on sodium. Biochemistry. 1998;37:8341–8355. PubMed

Shui X., Sines C.C., McFail-Isom L., VanDerveer D., Williams L.D. Structure of the potassium form of CGCGAATTCGCG: DNA deformation by electrostatic collapse around inorganic cations. Biochemistry. 1998;37:16877–16887. PubMed

Drew H., Samson S., Dickerson R.E. Structure of a B-DNA dodecamer at 16 K. Proc. Natl. Acad. Sci. U.S.A. 1982;79:4040–4044. PubMed PMC

Westhof E. Re-refinement of the B-dodecamer d(CGCGAATTCGCG) with a comparative analysis of the solvent in it and in the Z-hexamer d(5BrCG5BrCG5BrCG) J. Biomol. Struct. Dyn. 1987;5:581–600. PubMed

Holbrook S., Dickerson R., Kim S.-H. Anisotropic thermal-parameter refinement of the DNA dodecamer CGCGAATTCGCG by the segmented rigid-body method. Acta Crystallogr. B. 1985;41:255–262.

Wu Z., Delaglio F., Tjandra N., Zhurkin V., Bax A. Overall structure and sugar dynamics of a DNA dodecamer from homo- and heteronuclear dipolar couplings and (31)P chemical shift anisotropy. J. Biomol. Nmr. 2003;26:297–315. PubMed

Varnai P. alpha/gamma transitions in the B-DNA backbone. Nucleic Acids Res. 2002;30:5398–5406. PubMed PMC

Tian Y., Kayatta M., Shultis K., Gonzalez A., Mueller L.J., Hatcher M.E. 31P NMR investigation of backbone dynamics in DNA binding sites. J. Phys. Chem. B. 2009;113:2596–2603. PubMed PMC

Schwieters C.D., Clore G.M. A physical picture of atomic motions within the Dickerson DNA dodecamer in solution derived from joint ensemble refinement against NMR and large-angle X-ray scattering data. Biochemistry. 2007;46:1152–1166. PubMed

Dans P.D., Pérez A., Faustino I., Lavery R., Orozco M. Exploring polymorphisms in B-DNA helical conformations. Nucleic Acids Res. 2012;40:10668–10678. PubMed PMC

Schwarz G., Annals T., Mar N. Estimating the dimension of a model. Ann. Stat. 1978;6:461–464.

Djuranovic D., Hartmann B. DNA fine structure and dynamics in crystals and in solution: the impact of BI/BII backbone conformations. Biopolymers. 2004;73:356–368. PubMed

Wecker K. The role of the phosphorus BI-BII transition in protein-DNA recognition: the NF-kappaB complex. Nucleic Acids Res. 2002;30:4452–4459. PubMed PMC

Madhumalar A., Bansal M. Sequence preference for BI/BII conformations in DNA: MD and crystal structure data analysis. J. Biomol. Struct. Dyn. 2005;23:13–27. PubMed

Frederick C.A., Williams L.D., Ughetto G., Van der Marel G.A., Van Boom J.H., Rich A., Wang A.H.J. Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry. 1990;29:2538–2549. PubMed

Fei J., Ha T. Watching DNA breath one molecule at a time. Proc. Natl. Acad. Sci. U.S.A. 2013;110:17173–17174. PubMed PMC

Cubero E., Sherer E.C., Luque F.J., Orozco M., Laughton C.A. Observation of spontaneous base pair breathing events in the molecular dynamics simulation of a difluorotoluene-containing DNA oligonucleotide. J. Am. Chem. Soc. 1999;121:8653–8654.

Zgarbová M., Otyepka M., Šponer J., Lankaš F., Jurečka P. Base pair fraying in molecular dynamics simulations of DNA and RNA. J. Chem. Theory Comput. 2014;10:3177–3189. PubMed

Leontis N.B., Stombaugh J., Westhof E. The non-Watson-Crick base pairs and their associated isostericity matrices. Nucleic Acids Res. 2002;30:3497–3531. PubMed PMC

Galindo-Murillo R., Roe D.R., Cheatham T.E. On the absence of intrahelical DNA dynamics on the μs to ms timescale. Nat. Commun. 2014;5:5152. PubMed PMC

Galindo-Murillo R., Roe D.R., Cheatham T.E. Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC) Biochim. Biophys. Acta. 2015;1850:1041–1058. PubMed PMC

Histone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair

Importance of base-pair opening for mismatch recognition

Role of Inosine⁻Uracil Base Pairs in the Canonical RNA Duplexes

Assessing the Current State of Amber Force Field Modifications for DNA