Double stranded helical DNA and RNA are flexible molecules that can undergo global conformational fluctuations. Their bending, twisting and stretching deformabilities are of similar magnitude. However, recent single-molecule experiments revealed a striking qualitative difference indicating an opposite sign for the twist-stretch couplings of dsDNA and dsRNA [Lipfert et al. 2014. Proc. Natl. Acad. Sci. U.S.A. 111, 15408] that is not explained by existing models. Employing unconstrained Molecular Dynamics (MD) simulations we are able to reproduce the qualitatively different twist-stretch coupling for dsDNA and dsRNA in semi-quantitative agreement with experiment. Similar results are also found in simulations that include an external torque to induce over- or unwinding of DNA and RNA. Detailed analysis of the helical deformations coupled to twist indicate that the interplay of helical rise, base pair inclination and displacement from the helix axis upon twist changes are responsible for the different twist-stretch correlations. Overwinding of RNA results in more compact conformations with a narrower major groove and consequently reduced helical extension. Overwinding of DNA decreases the size of the minor groove and the resulting positive base pair inclination leads to a slender and more extended helical structure.

Department of Physics Center for Nanoscience Ludwig Maximilian University Munich 80799 Munich Germany

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo namesti 2 166 10 Prague Czech Republic Department of Physical and Macromolecular Chemistry Faculty of Science Charles University Prague Albertov 6 128 43 Prague Czech Republic

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

Physik Department T38 Technische Universität München James Franck Strasse D 85748 Garching Germany

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Rohs R., Jin X., West S.M., Joshi R., Honig B., Mann R.S. Origins of specificity in protein-DNA recognition. Annu. Rev. Biochem. 2010;79:233–269. PubMed PMC

Alexander R.W., Eargle J., Luthey-Schulten Z. Experimental and computational determination of tRNA dynamics. FEBS Lett. 2010;584:376–386. PubMed

Lee G., Bratkowski M.A., Ding F., Ke A., Ha T. Elastic coupling between RNA degradation and unwinding by an exoribonuclease. Science. 2012;336:1726–1729. PubMed PMC

Pinheiro A.V., Han D., Shih W.M., Yan H. Challenges and opportunities for structural DNA nanotechnology. Nat. Nanotechnol. 2011;6:763–772. PubMed PMC

Marko J.F., Siggia E.D. Bending and twisting elasticity of DNA. Macromolecules. 1994;27:881–998.

Bustamante C., Bryant Z., Smith SB. Ten years of tension: Single-molecule DNA mechanics. Nature. 2003;421:423–427. PubMed

Pérez A., Noy A., Lankas F., Luque F.J., Orozco M. The relative flexibility of B-DNA and A-RNA duplexes: database analysis. Nucleic Acids Res. 2004;32:6144–61451. PubMed PMC

Wereszczynski J., Andricioaei I. On structural transitions, thermodynamic equilibrium, and the phase diagram of DNA and RNA duplexes under torque and tension. Proc. Natl. Acad. Sci. U.S.A. 2006;103:16200–16205. PubMed PMC

Becker N., Everaers R. From rigid base pairs to semiflexible polymers: Coarse-graining DNA. Phys. Rev. E. 2007;76:021923. PubMed

Drsata T., Lankas F. Theoretical Models of DNA Flexibility. WIREs Comput. Mol. Sci. 2013;3:355–363.

Strick T.R., Allemand J.F., Bensimon D., Bensimon A., Croquette V. The elasticity of a single supercoiled DNA molecule. Science. 1996;271:1835–1837. PubMed

Moroz J.D., Nelson P. Torsional directed walks, entropic elasticity, and DNA twist stiffness. Proc. Natl. Acad. Sci. U.S.A. 1997;94:14418–14422. PubMed PMC

Allemand J.F., Bensimon D., Lavery R., Croquette V. Stretched and overwound DNA forms a Pauling-like structure with exposed bases. Proc. Natl. Acad. Sci. U.S.A. 1998;95:14152–14157. PubMed PMC

Bonin M., Zhu R., Klaue Y., Oberstrass J., Oesterschulze E., Nellen W. Analysis of RNA flexibility by scanning force spectroscopy. Nucleic Acids Res. 2002;30:e81. PubMed PMC

Gore J, Bryant Z., Nöllmann M., Le M.U., Cozzarelli N.R., Bustamante C. DNA overwinds when stretched. Nature. 2006;442:836–839. PubMed

Marko J.F. Torque and dynamics of linking number relaxation in stretched supercoiled DNA. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 2007;76:021926. PubMed

Sheinin M.Y., Wang M.D. Twist-stretch coupling and phase transition during DNA supercoiling. Phys. Chem. Chem. Phys. 2009;11:4800–4803. PubMed PMC

Lipfert J., Kerssemakers J.W., Jager T., Dekker N.H. Magnetic torque tweezers: measuring torsional stiffness in DNA and RecA-DNA filaments. Nat. Methods. 2010;7:977–980. PubMed

Sheinin M.Y., Forth S., Marko J.F., Wang M.D. Underwound DNA under tension: Structure, elasticity, and sequence-dependent behaviors. Phys. Rev. Lett. 2011;107:108102. PubMed PMC

Lipfert J., Wiggin M., Kerssemakers J.W., Pedaci F., Dekker N.H. Freely orbiting magnetic tweezers to directly monitor changes in the twist of nucleic acids. Nat. Commun. 2011;2:439–441. PubMed PMC

Bryant Z., Oberstrass F.C., Basu A. Recent developments in single-molecule DNA mechanics. Curr. Opin. Struct. Biol. 2012;22:304–312. PubMed PMC

Fujimoto B.S., Brewood G.P., Schurr J.M. Torsional rigidities of weakly strained DNAs. Biophys J. 2006;91:4166–4179. PubMed PMC

Bustamante C., Marko J.F., Siggia E.D., Smith S. Entropic elasticity of lambda-phage DNA. Science. 1994;265:1599–1600. PubMed

Smith S.B., Finzi L., Bustamante C. Direct mechanical measurements of the elasticity of single DNA molecules by using magnetic beads. Science. 1992;258:1122–1126. PubMed

Abels J.A., Moreno-Herrero F., van der Heijden T., Dekker C., Dekker N.H. Single-molecule measurements of the persistence length of double-stranded RNA. Biophys. J. 2005;88:2737–2744. PubMed PMC

Herrero-Galan E., Fuentes-Perez M.E., Carrasco C., Valpuesta J.M., Carrascosa J.L., Moreno-Herrero F., Arias-Gonzalez J.R. Mechanical identities of RNA and DNA double helices unveiled at the single-molecule level. J. Am. Chem. Soc. 2013;135:122–131. PubMed

Lipfert J., Skinner G.M., Keegstra J.M., Hensgens T., Jager T., Dulin D., Köber M., Yu Z., Donkers S.P., Chou F.C., Das R., Dekker N.H. Double-stranded RNA under force and torque: Similarities to and striking differences from double-stranded DNA. Proc. Natl. Acad. Sci. U.S.A. 2014;111:15408–15413. PubMed PMC

Fujimoto B.S., Schurr J.M. Dependence of the torsional rigidity of DNA on base composition. Nature. 1990;344:175–177. PubMed

Bryant Z., Stone M.D., Gore J., Smith S.B., Cozzarelli N.R., Bustamante C. Structural transitions and elasticity from torque measurements on DNA. Nature. 2003;424:338–341. PubMed

Smith S.B.,Cui,Y., Bustamante C. Overstretching B-DNA: the elastic response of individual double-stranded and single-stranded DNA molecules. Science. 1996;271:795–799. PubMed

Baumann C.G., Smith S.B., Bloomfield V.A., Bustamante C. Ionic effects on the elasticity of single DNA molecules. Proc. Natl. Acad. Sci. U.S.A. 1997;94:6185–6190. PubMed PMC

Bloomfield V.A., Crothers V.A., Tinoco I. Nucleic Acids: Structures, Properties, and Functions. Sausalito: University Science Books; 2000.

Lionnet T., Joubaud S., Lavery R., Bensimon D., Croquette V. Wringing out DNA. Phys. Rev. Lett. 2006;96:178102. PubMed

Lionnet T, Lankas F. Sequence-dependent twist-stretch coupling in DNA. Biophys J. 2007;92:30–32. PubMed PMC

Kamien R.D., Lubensky T.C., Nelson P., Ohern C.S. Direct determination of DNA twist-stretch coupling. Europhys. Lett. 1997;38:237–242.

Marko J.F. Stretching must twist DNA. Europhys. Lett. 1997;38:183–188.

Moroz J.D., Nelson P. Entropic elasticity of twist-storing polymers. Macromolecules. 1998;31:6333–6347.

Olsen K., Bohr J. The geometrical origin of the strain-twist coupling in double helices. AIP Adv. 2011;1:012108.

Kosikov K.M., Gorin A.A., Zhurkin V.B., Olson W.K. DNA stretching and compression: Large-scale simulations of double helical structures. J. Mol. Biol. 1999;289:1301–1326. PubMed

Chou F.C., Lipfert J., Das R. Blind predictions of DNA and RNA tweezers experiments with force and torque. PLoS Comput. Biol. 2014;10:e1003756. PubMed PMC

Durickovic B., Goriely A., Maddocks J.H. Twist and stretch of helices explained via the Kirchhoff-Love rod model of elastic filaments. Phys. Rev. Lett. 2013;111:108103. PubMed

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

Sponer J., Bana P., Jureca P., Zgarbova M., Kuhrova P., Havrila M., Krepl M., Stadlbauer R., Otyepka M. Molecular dynamics simulations of nucleic acids. From tetranucleotides to the ribosome. J. Phys. Chem. Lett. 2014;5:1771–1782. PubMed

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

Lankas F. Modelling Nucleic Acid Structure and Flexibility: From Atomic to Mesoscopic Scale. In: Schlick T, editor. Innovations in Biomolecular Modeling and Simulations. Vol. 2. London: Royal Society of Chemistry; 2012. pp. 3–32.

Drsata T., Zgarbova M., Spackova N., Jurecka P., Sponer J., Lankas F. Mechanical model of DNA allostery. J. Phys. Chem. Lett. 2014;5:3831–3835. PubMed

Dixit S.B., Beveridge D.L., Case D.A., Cheatham T.E. 3rd, Giudice E., Lankas F., Lavery R., Maddocks J.H., Osman R., Sklenar H., et al. Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. II: sequence context effects on the dynamical structures of the 10 unique dinucleotide steps. Biophys J. 2005;89:3721–3740. PubMed PMC

Lavery R., Zakrzewska K., Beveridge D., Bishop T.C., Case D.A., Cheatham T. 3rd, Dixit S., Jayaram B., Lankas F., Laughton C., et al. A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA. Nucleic Acids Res. 2010;38:299–313. PubMed PMC

Pasi M., Maddocks J.H., Beveridge D., Bishop T.C., Case D.A., Cheatham T. 3rd, 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

Kara M., Zacharias M. Theoretical studies of nucleic acid folding. WIREs Comput. Mol. Sci. 2013;4:116–126.

Lankas F., Sponer J., Langowski J., Cheetham T.E. DNA base pair step deformabilities inferred from molecular dynamics simulations. Biophys. J. 2003;85:2872–2883. PubMed PMC

Case D.A., Darden T.A., Cheatham T.E., Simmerling C.L., Wang J., Duke R.E., Luo R., Walker R.C., Zhang W., Merz K.M., et al. Amber12. San Francisco: University of California; 2012.

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.

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

Zgarbová M., Otyepka M., Sponer J., Mládek A., Banáš P., Cheatham T.E. 3rd, Jurečka P. Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles. J. Chem. Theory Comput. 2011;7:2886–2902. PubMed PMC

Zgarbová M., Luque F.J., Sponer J., Cheatham T.E., 3rd, Otyepka M., Jurečka P. Toward Improved Description of DNA Backbone: Revisiting Epsilon and Zeta Torsion Force Field Parameters. J. Chem. Theory Comput. 2013;9:2339–2354. PubMed PMC

Kannan S., Kohlhoff K., Zacharias M. B-DNA Under Stress: Over and Un-twisting of DNA during Molecular Dynamics Simulations. Biophys. J. 2006;25:2956–2965. 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

Lu X.-J., Olson W.K. 3DNA: A Software package for the Analysis, Rebuilding and Visualization of Three-Dimensional Nucleic Acid Structures. Nucleic Acids Res. 2003;31:5108–5121. PubMed PMC

Lavery R., Zakrzewska K., Sklenar H. JUMNA (junction minimization of nucleic acids) Comput. Phys. Comm. 1995;91:135–158.

Zacharias M. Comparison of molecular dynamics and harmonic mode calculations on RNA. Biopolymers. 2000;54:547–560. PubMed

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