Heteronuclear and homonuclear direct (D) and indirect (J) spin-spin interactions are important sources of structural information about nucleic acids (NAs). The Hamiltonians for the D and J interactions have the same functional form; thus, the experimentally measured apparent spin-spin coupling constant corresponds to a sum of J and D. In biomolecular NMR studies, it is commonly presumed that the dipolar contributions to Js are effectively canceled due to random molecular tumbling. However, in strong magnetic fields, such as those employed for NMR analysis, the tumbling of NA fragments is anisotropic because the inherent magnetic susceptibility of NAs causes an interaction with the external magnetic field. This motional anisotropy is responsible for non-zero D contributions to Js. Here, we calculated the field-induced D contributions to 33 structurally relevant scalar coupling constants as a function of magnetic field strength, temperature and NA fragment size. We identified two classes of Js, namely (1)JCH and (3)JHH couplings, whose quantitative interpretation is notably biased by NA motional anisotropy. For these couplings, the magnetic field-induced dipolar contributions were found to exceed the typical experimental error in J-coupling determinations by a factor of two or more and to produce considerable over- or under-estimations of the J coupling-related torsion angles, especially at magnetic field strengths >12 T and for NA fragments longer than 12 bp. We show that if the non-zero D contributions to J are not properly accounted for, they might cause structural artifacts/bias in NA studies that use solution NMR spectroscopy.

Bijvoet Center for Biomolecular Research Utrecht University Padualaan 8 3584 CH Utrecht The Netherlands

Central European Institute of Technology Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Faculty of Science Masaryk University Kotlářská 2 611 37 Brno Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Flemingovo náměstí 542 2 166 10 Praha 6 Czech Republic

Institute of Physics Academy of Sciences of the Czech Republic v v i Na Slovance 2 182 21 Prague 8 Czech Republic

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J Biomol NMR. 2016 May;65(1):49. doi: 10.1007/s10858-016-0034-0. PubMed

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Al-Hashimi HM. NMR studies of nucleic acid dynamics. J Magn Reson. 2013;237:191–204. doi: 10.1016/j.jmr.2013.08.014. PubMed DOI PMC

Al-Hashimi HM, Gorin A, Majumdar A, Patel DJ. Alignment of the HTLV-I Rex peptide bound to its target RNA aptamer from magnetic field-induced residual dipolar couplings and intermolecular hydrogen bonds. J Am Chem Soc. 2001;123:3179–3180. doi: 10.1021/ja004133w. PubMed DOI

Al-Hashimi HM, Majumdar A, Gorin A, Kettani A, Skripkin E, Patel DJ. Field- and phage-induced dipolar couplings in a homodimeric DNA quadruplex, relative orientation of G center dot(C-A) triad and G-tetrad motifs and direct determination of C2 symmetry axis orientation. J Am Chem Soc. 2001;123:633–640. doi: 10.1021/ja003379y. PubMed DOI

Al-Hashimi HM, Tolman JR, Majumdar A, Gorin A, Patel DJ. Determining stoichiometry in homomultimeric nucleic acid complexes using magnetic field induced residual dipolar couplings. J Am Chem Soc. 2001;123:5806–5807. doi: 10.1021/ja0105865. PubMed DOI

Alkorta I, Elguero J, Denisov GS. A review with comprehensive data on experimental indirect scalar NMR spin–spin coupling constants across hydrogen bonds. Magn Reson Chem. 2008;46:599–624. doi: 10.1002/mrc.2209. PubMed DOI

Bax A, Tjandra N. High-resolution heteronuclear NMR of human ubiquitin in an aqueous liquid crystalline medium. J Biomol NMR. 1997;10:289–292. doi: 10.1023/A:1018308717741. PubMed DOI

Bax A, Vuister GW, Grzesiek S, Delaglio F, Wang AC, Tschudin R, Zhu G. Measurement of homonuclear and heteronuclear J-couplings from quantitative J-correlation. Method Enzymol. 1994;239:79–105. doi: 10.1016/S0076-6879(94)39004-5. PubMed DOI

Becke AD. Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys. 1993;98:5648–5652. doi: 10.1063/1.464913. DOI

Brandes R, Kearns DR. Magnetic ordering of DNA liquid crystals. Biochemistry. 1986;25:5890–5895. doi: 10.1021/bi00368a008. PubMed DOI

Bruschweiler R, Case DA. Adding harmonic motion to the Karplus relation for Spin-Spin coupling. J Am Chem Soc. 1994;116:11199–11200. doi: 10.1021/ja00103a062. DOI

Bryce DL, Boisbouvier J, Bax A. Experimental and theoretical determination of nucleic acid magnetic susceptibility: importance for the study of dynamics by field-induced residual dipolar couplings. J Am Chem Soc. 2004;126:10820–10821. doi: 10.1021/ja047179o. PubMed DOI

Case DA, et al. AMBER 10. San Francisco: University of California; 2008.

Cheeseman JR, Trucks GW, Keith TA, Frisch MJ. A comparison of models for calculating nuclear magnetic resonance shielding tensors. J Chem Phys. 1996;104:5497–5509. doi: 10.1063/1.471789. DOI

Clore GM, Starich MR, Gronenborn AM. Measurement of residual dipolar couplings of macromolecules aligned in the nematic phase of a colloidal suspension of rod-shaped viruses. J Am Chem Soc. 1998;120:10571–10572. doi: 10.1021/ja982592f. DOI

Clowney L, Jain SC, Srinivasan AR, Westbrook J, Olson WK, Berman HM. Geometric parameters in nucleic acids: nitrogenous bases. J Am Chem Soc. 1996;118:509–518. doi: 10.1021/ja952883d. DOI

Ditchfield R, Hehre WJ, Pople JA. Self-consistent molecular-orbital methods. IX. An extended gaussian-type basis for molecular-orbital studies of organic molecules. J Chem Phys. 1971;54:724–728. doi: 10.1063/1.1674902. DOI

Fiala R, Špačková N, Foldynová-Trantírková S, Šponer J, Sklenář V, Trantírek L. NMR cross-correlated relaxation rates reveal ion coordination sites in DNA. J Am Chem Soc. 2011;133:13790–13793. doi: 10.1021/ja202397p. PubMed DOI

Fonville JM, et al. Chemical shifts in nucleic acids studied by density functional theory calculations and comparison with experiment. Chem Eur J. 2012;18:12372–12387. doi: 10.1002/chem.201103593. PubMed DOI

Frisch MJ, et al. Gaussian 09 Revision A.02. Wallingford: Gaussian, Inc; 2009.

Griesinger C, Sorensen OW, Ernst RR. Two-dimensional correlation of connected NMR transitions. J Am Chem Soc. 1985;107:6394–6396. doi: 10.1021/ja00308a042. DOI

Hansel R, Lohr F, Foldynova-Trantirkova S, Bamberg E, Trantirek L, Dotsch V. The parallel G-quadruplex structure of vertebrate telomeric repeat sequences is not the preferred folding topology under physiological conditions. Nucleic Acids Res. 2011;39:5768–5775. doi: 10.1093/nar/gkr174. PubMed DOI PMC

Harbison GS. Interference between J-couplings and cross-relaxation in solution NMR spectroscopy: consequences for macromolecular strcuture determination. J Am Chem Soc. 1993;115:3026–3027. doi: 10.1021/ja00060a081. DOI

Iizuka E. Orientation of liquid-crystals of polyribonucleotide complexes in a static magnetic-field. Polym J. 1978;10:235–237. doi: 10.1295/polymj.10.235. DOI

Iizuka E, Kondo Y. Magnetic-field orientation of the liquid-crystals of polyribonucleotide complexes Mol Cryst Liq Cryst. 1979;51:285–293. doi: 10.1080/00268947908084714. DOI

Iizuka E, Yang JT. Formation of liquid-crystals of polyribonculeotide complexes. Abstr Pap Am Chem Soc. 1977;174:93.

Ippel JH, et al. Heteronuclear scalar couplings in the bases and sugar rings of nucleic acids: their determination and application in assignment and conformational analysis. Magn Reson Chem. 1996;34:S156–S176. doi: 10.1002/(SICI)1097-458X(199612)34:13<S156::AID-OMR68>3.0.CO;2-U. DOI

Kontaxis G, Clore GM, Bax A. Evaluation of cross-correlation effects and measurement of one-bond couplings in proteins with short transverse relaxation times. J Magn Reson. 2000;143:184–196. doi: 10.1006/jmre.1999.1979. PubMed DOI

Kung HC, Wang KY, Goljer I, Bolton PH. Magnetic alignment of duplex and quadruplex DNAs. J Magn Reson. 1995;109:323–325. doi: 10.1006/jmrb.1995.9987. PubMed DOI

Lu XJ. 3DNA: a software package for the analysis, rebuilding and visualization of three-dimensional nucleic acid structures. Nucleic Acids Res. 2003;31:5108–5121. doi: 10.1093/nar/gkg680. PubMed DOI PMC

Meissner A, Duus J, Sørensen O. Integration of spin-state-selective excitation into 2D NMR correlation experiments with heteronuclear ZQ/2Q π rotations for 1 JXH. J Biomol NMR. 1997;10:89–94. doi: 10.1023/A:1018331001961. PubMed DOI

Meissner A, Jø Duus, Sørensen OW. Spin-state-selective excitation. Application for E.COSY-type measurement of JHH coupling constants. J Magn Reson. 1997;128:92–97. doi: 10.1006/jmre.1997.1213. DOI

Miertus S, Tomasi J. Approximate evaluations of the electrostatic free energy and internal energy changes in solution processes. Chem Phys. 1982;65:239–245. doi: 10.1016/0301-0104(82)85072-6. DOI

Miertuš S, Scrocco E, Tomasi J. Electrostatic interaction of a solute with a continuum. A direct utilizaion of AB initio molecular potentials for the prevision of solvent effects. Chem Phys. 1981;55:117–129. doi: 10.1016/0301-0104(81)85090-2. DOI

Munzarova ML, Sklenar V. DFT analysis of NMR scalar interactions across the glycosidic bond in DNA. J Am Chem Soc. 2003;125:3649–3658. doi: 10.1021/ja028931t. PubMed DOI

Ottiger M, Delaglio F, Bax A. Measurement of J and dipolar douplings from simplified two-dimensional NMR spectra. J Magn Reson. 1998;131:373–378. doi: 10.1006/jmre.1998.1361. PubMed DOI

Rill RL. Liquid crystalline phases in concentrated aqueous solutions of Na+ DNA. PNAS. 1986;83:342–346. doi: 10.1073/pnas.83.2.342. PubMed DOI PMC

Rill RL, Hilliard PR, Levy GC. Spontaneous ordering of DNA. Effects of intermolecular interactions on DNA motional dynamics monitored by 13C and 31P nuclear magnetic resonance spectroscopy. J Biol Chem. 1983;258:250–256. PubMed

Roberts GC. NMR of macromolecules: a practical approach. UK: Oxford University Press; 1993.

Robinson C. Liquid-crystalline structures in polypeptide solutions. Tetrahedron. 1961;13:219–234. doi: 10.1016/S0040-4020(01)92215-X. DOI

Rückert M, Otting G. Alignment of biological macromolecules in novel nonionic liquid crystalline media for NMR experiments. J Am Chem Soc. 2000;122:7793–7797. doi: 10.1021/ja001068h. DOI

Sass H-J, Musco G, Stahl S, Wingfield P, Grzesiek S. Solution NMR of proteins within polyacrylamide gels: diffusional properties and residual alignment by mechanical stress or embedding of oriented purple membranes. J Biomol NMR. 2000;18:303–309. doi: 10.1023/A:1026703605147. PubMed DOI

Senechal E, Maret G, Dransfeld K. Long-range order of nucleic-acids in aqueous-solutions. Int J Biol Macromol. 1980;2:256–262. doi: 10.1016/0141-8130(80)90085-9. DOI

Su X-C, McAndrew K, Huber T, Otting G. Lanthanide-binding peptides for NMR measurements of residual dipolar couplings and paramagnetic effects from multiple angles. J Am Chem Soc. 2008;130:1681–1687. doi: 10.1021/ja076564l. PubMed DOI

Sychrovský V, Šponer J, Trantírek L, Schneider B. Indirect NMR spin–spin coupling constants 3J(P, C) and 2J(P, H) across the P–O···H–C link can be used for structure determination of nucleic acids. J Am Chem Soc. 2006;128:6823–6828. doi: 10.1021/ja0551180. PubMed DOI

Tjandra N, Bax A. Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. Science. 1997;278:1111–1114. doi: 10.1126/science.278.5340.1111. PubMed DOI

Tjandra N, Grzesiek S, Bax A. Magnetic field dependence of nitrogen-proton J splittings in N-15-enriched human ubiquitin resulting from relaxation interference and residual dipolar coupling. J Am Chem Soc. 1996;118:6264–6272. doi: 10.1021/ja960106n. DOI

Trantirek L, Stefl R, Masse JE, Feigon J, Sklenar V. Determination of the glycosidic torsion angles in uniformly C-13-labeled nucleic acids from vicinal coupling constants (3)J(C2/4-H1′) and (3)J(C6/8-H1′) J Biomol NMR. 2002;23:1–12. doi: 10.1023/A:1015389118506. PubMed DOI

Trohalaki S, Brian AA, Frisch HL, Lerman LS. Scaling of the equilibrium sedimentation distribution in dense DNA solutions. Biophys J. 1984;45:777–782. doi: 10.1016/S0006-3495(84)84221-6. PubMed DOI PMC

Tycko R, Blanco FJ, Ishii Y. Alignment of biopolymers in strained gels: a new way to create detectable dipole–dipole couplings in high-resolution biomolecular NMR. J Am Chem Soc. 2000;122:9340–9341. doi: 10.1021/ja002133q. DOI

van Buuren BN, Schleucher J, Wittmann V, Griesinger C, Schwalbe H, Wijmenga SS. NMR spectroscopic determination of the solution structure of a branched nucleic acid from residual dipolar couplings by using isotopically labeled nucleotides. Angew Chem Int Ed Engl. 2004;43:187–192. doi: 10.1002/anie.200351632. PubMed DOI

Vogeli B, Yao L, Bax A. Protein backbone motions viewed by intraresidue and sequential HN-Halpha residual dipolar couplings. J Biomol NMR. 2008;41:17–28. doi: 10.1007/s10858-008-9237-3. PubMed DOI PMC

Vokacova Z, Bickelhaupt FM, Sponer J, Sychrovsky V. Structural interpretation of J coupling constants in guanosine and deoxyguanosine: modeling the effects of sugar pucker, backbone conformation, and base pairing. J Phys Chem A. 2009;113:8379–8386. doi: 10.1021/jp902473v. PubMed DOI

Wang AC, Bax A. Determination of the backbone dihedral angles phi in human ubiquitin from reparametrized empirical Karplus equations. J Am Chem Soc. 1996;118:2483–2494. doi: 10.1021/ja9535524. DOI

Wijmenga SS, van Buuren BNM. The use of NMR methods for conformational studies of nucleic acids. Prog Nucl Magn Reson Spectrosc. 1998;32:287–387. doi: 10.1016/S0079-6565(97)00023-X. DOI

Wöhnert J, Franz KJ, Nitz M, Imperiali B, Schwalbe H. Protein alignment by a coexpressed lanthanide-binding tag for the measurement of residual dipolar couplings. J Am Chem Soc. 2003;125:13338–13339. doi: 10.1021/ja036022d. PubMed DOI

Wollinski K, Hinton JF, Pulay P. Efficient implementation of the gauge-independent atomic orbital method for NMR chemical-shift calculations. J Am Chem Soc. 1990;112:8251–8260. doi: 10.1021/ja00179a005. DOI

Yao L, Ying J, Bax A. Improved accuracy of 15 N–1H scalar and residual dipolar couplings from gradient-enhanced IPAP-HSQC experiments on protonated proteins. J Biomol NMR. 2009;43:161–170. doi: 10.1007/s10858-009-9299-x. PubMed DOI PMC

Zhang Q, Al-Hashimi HM. Extending the NMR spatial resolution limit for RNA by motional couplings. Nat Methods. 2008;5:243–245. doi: 10.1038/nmeth.1180. PubMed DOI

Zhang Q, Throolin R, Pitt SW, Serganov A, Al-Hashimi HM. Probing motions between equivalent RNA domains using magnetic field induced residual dipolar couplings: accounting for correlations between motions and alignment. J Am Chem Soc. 2003;125:10530–10531. doi: 10.1021/ja0363056. PubMed DOI

Zhou HJ, Vermeulen A, Jucker FM, Pardi A. Incorporating residual dipolar couplings into the NMR solution structure determination of nucleic acids. Biopolymers. 1999;52:168–180. doi: 10.1002/1097-0282(1999)52:4<168::AID-BIP1002>3.0.CO;2-7. PubMed DOI

Zweckstetter M, Bax A. Characterization of molecular alignment in aqueous suspensions of Pf1 bacteriophage. J Biomol NMR. 2001;20:365–377. doi: 10.1023/A:1011263920003. PubMed DOI