Ionic liquids (ILs) have become nearly ubiquitous solvents and their interactions with biomolecules has been a focus of study. Here, we used the fluorescence emission of DAPI, a groove binding fluorophore, coupled with molecular dynamics (MD) simulations to report on interactions between imidazolium chloride ([Imn,1]+) ionic liquids and a synthetic DNA oligonucleotide composed entirely of T/A bases (7(TA)) to elucidate the effects ILs on a model DNA duplex. Spectral shifts on the order of 500-1000 cm-1, spectral broadening (~1000 cm-1), and excitation and emission intensity ratio changes combine to give evidence of an increased DAPI environment heterogeneity on added IL. Fluorescence lifetimes for DAPI/IL solutions yielded two time constants 0.15 ns (~80% to 60% contribution) and 2.36-2.71 ns for IL up to 250 mM. With DNA, three time constants were required that varied with added IL (0.33-0.15 ns (1-58% contribution), ~1.7-1.0 ns (~5% contribution), and 3.8-3.6 ns (94-39% contribution)). MD radial distribution functions revealed that π-π stacking interactions between the imidazolium ring were dominant at lower IL concentration and that electrostatic and hydrophobic interactions become more prominent as IL concentration increased. Alkyl chain alignment with DNA and IL-IL interactions also varied with IL. Collectively, our data showed that, at low IL concentration, IL was primarily bound to the DNA minor groove and with increased IL concentration the phosphate regions and major groove binding sites were also important contributors to the complete set of IL-DNA duplex interactions.

Department of Chemistry and Biochemistry SUNY Brockport Brockport NY 14420 USA

Faculty of Science University of South Bohemia in České Budějovice Branišovská 1645 31A 37005 Ceske Budejovice Czech Republic

Laboratory of Structural Biology and Bioinformatics Institute of Microbiology of the Czech Academy of Sciences Zámek 136 37333 Nove Hrady Czech Republic

Zobrazit více v PubMed

LaBean T.H., Li H. Constructing novel materials with DNA. Nano Today. 2007;2:26–35. doi: 10.1016/S1748-0132(07)70056-7. DOI

Vijayaraghavan R., Izgorodin A., Ganesh V., Surianarayanan M., MacFarlane D.R. Long-Term Structural and Chemical Stability of DNA in Hydrated Ionic Liquids. Angew. Chemie Int. Ed. 2010;49:1631–1633. doi: 10.1002/anie.200906610. PubMed DOI

Heller M.J. DNA Microarray Technology: Devices, Systems, and Applications. Ann. Rev. Biomed. Engineer. 2002;4:129–153. doi: 10.1146/annurev.bioeng.4.020702.153438. PubMed DOI

Rezki N., Al-blewi F.F., Al-Sodies S.A., Alnuzha A.K., Messali M., Ali I., Aouad M.R. Synthesis, Characterization, DNA Binding, Anticancer, and Molecular Docking Studies of Novel Imidazolium-Based Ionic Liquids with Fluorinated Phenylacetamide Tethers. ACS Omega. 2020;5:4807–4815. doi: 10.1021/acsomega.9b03468. PubMed DOI PMC

Al-Sodies S.A., Aouad M.R., Ihmaid S., Aljuhani A., Messali M., Ali I., Rezki N. Microwave and conventional synthesis of ester based dicationic pyridinium ionic liquids carrying hydrazone linkage: DNA binding, anticancer and docking studies. J. Mol. Struct. 2020;1207:127756. doi: 10.1016/j.molstruc.2020.127756. DOI

Revathi N., Sankarganesh M., Dhaveethu Raja J., Vinoth Kumar G.G., Sakthivel A., Rajasekaran R. Bio-active mixed ligand Cu(II) and Zn(II) complexes of pyrimidine derivative Schiff base: DFT calculation, antimicrobial, antioxidant, DNA binding, anticancer and molecular docking studies. J. Biomolec. Struct. Dyn. 2021;39:3012–3024. doi: 10.1080/07391102.2020.1759454. PubMed DOI

Alraqa S.Y., Alharbi K., Aljuhani A., Rezki N., Aouad M.R., Ali I. Design, click conventional and microwave syntheses, DNA binding, docking and anticancer studies of benzotriazole-1,2,3-triazole molecular hybrids with different pharmacophores. J. Mol. Struct. 2021;1225:129192. doi: 10.1016/j.molstruc.2020.129192. DOI

Walden P. Ueber die Molekulargrösse und elektrieshe Leitfähigkeit einiger gazehmolzenen Salze. Bull. Acad. Imper. Sci. St. Petersbg. 1914;8:405–422.

Benedetto A., Ballone P. Room-Temperature Ionic Liquids and Biomembranes: Setting the Stage for Applications in Pharmacology, Biomedicine, and Bionanotechnology. Langmuir. 2018;34:9579–9597. doi: 10.1021/acs.langmuir.7b04361. PubMed DOI

Somers A.E., Howlett P.C., MacFarlane D.R., Forsyth M. A Review of Ionic Liquid Lubricants. Lubricants. 2013;1:3–21. doi: 10.3390/lubricants1010003. DOI

Lei Z., Chen B., Koo Y.-M., MacFarlane D.R. Introduction: Ionic Liquids. Chem. Rev. 2017;117:6633–6635. doi: 10.1021/acs.chemrev.7b00246. PubMed DOI

Weingärtner H. Understanding Ionic Liquids at the Molecular Level: Facts, Problems, and Controversies. Angew. Chem. Int. Ed. 2008;47:654–670. doi: 10.1002/anie.200604951. PubMed DOI

Rogers R.D., Seddon K.R. Ionic Liquids--Solvents of the Future? Science. 2003;302:792–793. doi: 10.1126/science.1090313. PubMed DOI

Xu W., Angell C.A. Solvent-Free Electrolytes with Aqueous Solution-Like Conductivities. Science. 2003;302:422–425. doi: 10.1126/science.1090287. PubMed DOI

Seddon K.R. A taste of the future. Nat. Mater. 2003;2:363–365. doi: 10.1038/nmat907. PubMed DOI

Uddin M.N., Basak D., Hopefl R., Minofar B. Potential Application of Ionic Liquids in Pharmaceutical Dosage Forms for Small Molecule Drug and Vaccine Delivery System. J. Pharm. Pharm. Sci. 2020;23:158–176. doi: 10.18433/jpps30965. PubMed DOI

He Y., Shang Y., Liu Z., Shao S., Liu H., Hu Y. Interactions between ionic liquid surfactant [C12mim]Br and DNA in dilute brine. Colloid Surf. B Biointerfaces. 2013;101:398–404. doi: 10.1016/j.colsurfb.2012.07.027. PubMed DOI

Jumbri K., Abdul Rahman M.B., Abdulmalek E., Ahmad H., Micaelo N.M. An insight into structure and stability of DNA in ionic liquids from molecular dynamics simulation and experimental studies. Phys. Chem. Chem. Phys. 2014;16:14036–14046. doi: 10.1039/C4CP01159G. PubMed DOI

Wang X., Cui F. Binding characteristics of imidazolium-based ionic liquids with calf thymus DNA: Spectroscopy studies. J. Fluorine Chem. 2018;213:68–73. doi: 10.1016/j.jfluchem.2018.07.005. DOI

Chandran A., Ghoshdastidar D., Senapati S. Groove Binding Mechanism of Ionic Liquids: A Key Factor in Long-Term Stability of DNA in Hydrated Ionic Liquids? J. Am. Chem. Soc. 2012;134:20330–20339. doi: 10.1021/ja304519d. PubMed DOI

Khadieva A., Mostovaya O., Padnya P., Kalinin V., Grishaev D., Tumakov D., Stoikov I. Arylamine Analogs of Methylene Blue: Substituent Effect on Aggregation Behavior and DNA Binding. Int. J. Molec. Sci. 2021;22:5847. doi: 10.3390/ijms22115847. PubMed DOI PMC

Mostovaya O., Padnya P., Shiabiev I., Mukhametzyanov T., Stoikov I. PAMAM-calix-dendrimers: Synthesis and Thiacalixarene Conformation Effect on DNA Binding. Int. J. Molec. Sci. 2021;22:11901. doi: 10.3390/ijms222111901. PubMed DOI PMC

Kapuściński J., Szer W. Interactions of 4′, 6-diamidine-2-phenylindole with synthetic polynucleotides. Nucleic Acids Res. 1979;6:3519–3534. doi: 10.1093/nar/6.11.3519. PubMed DOI PMC

Eriksson S., Kim S.K., Kubista M., Norden B. Binding of 4’,6-diamidino-2-phenylindole (DAPI) to AT regions of DNA: Evidence for an allosteric conformational change. Biochemistry. 1993;32:2987–2998. doi: 10.1021/bi00063a009. PubMed DOI

Barcellona M.L., Favilla R., Von Berger J., Avitabile M., Ragusa N., Masotti L. DNA-4′-6-diamidine-2-phenylindole interactions: A comparative study employing fluorescence and ultraviolet spectroscopy. Arch. Biochem. Biophys. 1986;250:48–53. doi: 10.1016/0003-9861(86)90700-9. PubMed DOI

Kapuscinski J. DAPI: A DNA-Specific Fluorescent Probe. Biotechnic Histochem. 1995;70:220–233. doi: 10.3109/10520299509108199. PubMed DOI

Larsen T.A., Goodsell D.S., Cascio D., Grzeskowiak K., Dickerson R.E. The Structure of DAPI Bound to DNA. J. Biomolec. Struct. Dyn. 1989;7:477–491. doi: 10.1080/07391102.1989.10508505. PubMed DOI

Kapuściński J., Skoczylas B. Fluorescent complexes of DNA with DAPI 4′,6-diamidine-2-phenyl indole 2HCl or DCI 4′,6-dicarboxyamide-2-pnenyl indole. Nucleic Acids Res. 1978;5:3775–3800. doi: 10.1093/nar/5.10.3775. PubMed DOI PMC

Lin M.S., Comings D.E., Alfi O.S. Optical studies of the interaction of 4′-6-diamidino-2-phenylindole with DNA and metaphase chromosomes. Chromsoma. 1977;60:15–25. doi: 10.1007/BF00330407. PubMed DOI

Barcellona M.L., Gratton E. The fluorescence properties of a DNA probe. Euro. Biophys. J. 1990;17:315–323. doi: 10.1007/BF00258380. PubMed DOI

Barcellona M.L., Cardiel G., Gratton E. Time-resolved fluorescence of DAPI in solution and bound to polydeoxynucleotides. Biochem. Biophys. Res. Commun. 1990;170:270–280. doi: 10.1016/0006-291X(90)91270-3. PubMed DOI

Barcellona M.L., Gratton E. Fluorescence lifetime distributions of DNA-4′,6-diamidino-2-phenylindole complex. Biochim. Biophys Acta. 1989;993:174–178. doi: 10.1016/0304-4165(89)90160-8. PubMed DOI

Boger D.L., Fink B.E., Brunette S.R., Tse W.C., Hedrick M.P. A Simple, High-Resolution Method for Establishing DNA Binding Affinity and Sequence Selectivity. J. Am. Chem. Soc. 2001;123:5878–5891. doi: 10.1021/ja010041a. PubMed DOI

Ding Y., Zhang L., Xie J., Guo R. Binding Characteristics and Molecular Mechanism of Interaction between Ionic Liquid and DNA. J. Phys. Chem. B. 2010;114:2033–2043. doi: 10.1021/jp9104757. PubMed DOI

Reis L.A., Rocha M.S. DNA interaction with DAPI fluorescent dye: Force spectroscopy decouples two different binding modes. Biopolymers. 2017;107:e23015. doi: 10.1002/bip.23015. PubMed DOI

Keppeler N., Galgano P.D., da Silva Santos S., Malek N.I., El Seoud O.A. On the effects of head-group volume on the adsorption and aggregation of 1-(n-hexadecyl)-3-Cm-imidazolium bromide and chloride surfactants in aqueous solutions. J. Mol. Liq. 2021;328:115478. doi: 10.1016/j.molliq.2021.115478. DOI

El Seoud O.A., Pires P.A.R., Abdel-Moghny T., Bastos E.L. Synthesis and micellar properties of surface-active ionic liquids: 1-Alkyl-3-methylimidazolium chlorides. J. Colloid. Int. Sci. 2007;313:296–304. doi: 10.1016/j.jcis.2007.04.028. PubMed DOI

LaRocca M.M., Baker G.A., Heitz M.P. Assessing rotation and solvation dynamics in ethaline deep eutectic solvent and its solutions with methanol. J. Chem. Phys. 2021;155:034505. doi: 10.1063/5.0056653. PubMed DOI

Barra K.M., Sabatini R.P., McAtee Z.P., Heitz M.P. Solvation and Rotation Dynamics in the Trihexyl(tetradecyl)phosphonium Chloride Ionic Liquid/Methanol Cosolvent System. J. Phys. Chem. B. 2014;118:12979–12992. doi: 10.1021/jp5092784. PubMed DOI

Case D.A., Darden T.A., Cheatham T.E., Simmerling C.L., Wang J., Duke R.E., Luo R., Crowley M.R., Walker R.C., Zhang W., et al. Amber 10. University of California; San Francisco, CA, USA: 2008.

Lindorff-Larsen K., Piana S., Palmo K., Maragakis P., Klepeis J.L., Dror R.O., Shaw D.E. Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins. 2010;78:1950–1958. doi: 10.1002/prot.22711. PubMed DOI PMC

Martínez J.M., Martínez L. Packing optimization for automated generation of complex system’s initial configurations for molecular dynamics and docking. J. Comput. Chem. 2003;24:819–825. doi: 10.1002/jcc.10216. PubMed DOI

Martínez L., Andrade R., Birgin E.G., Martínez J.M. PACKMOL: A package for building initial configurations for molecular dynamics simulations. J. Comput. Chem. 2009;30:2157–2164. doi: 10.1002/jcc.21224. PubMed DOI

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. doi: 10.1063/1.445869. DOI

Hess B., Bekker H., Berendsen H.J.C., Fraaije J.G.E.M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 1997;18:1463–1472. doi: 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H. DOI

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. doi: 10.1063/1.464397. DOI

Bussi G., Donadio D., Parrinello M. Canonical sampling through velocity rescaling. J. Chem. Phys. 2007;126:014101. doi: 10.1063/1.2408420. PubMed DOI

Abraham M.J., Murtola T., Schulz R., Páll S., Smith J.C., Hess B., Lindahl E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25. doi: 10.1016/j.softx.2015.06.001. DOI

Páll S., Abraham M.J., Kutzner C., Hess B., Lindahl E. In: Solving Software Challenges for Exascale. 1st ed. Markidis S., Laure E., editors. Springer International Publishing; Cham, Switzerland: 2015.

Pronk S., Páll S., Schulz R., Larsson P., Bjelkmar P., Apostolov R., Shirts M.R., Smith J.C., Kasson P.M., van der Spoel D., et al. GROMACS 4.5: A high-throughput and highly parallel open-source molecular simulation toolkit. Bioinfomatics. 2013;29:845–854. doi: 10.1093/bioinformatics/btt055. PubMed DOI PMC

Hess B., Kutzner C., van der Spoel D., Lindahl E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput. 2008;4:435–447. doi: 10.1021/ct700301q. PubMed DOI

Van Der Spoel D., Lindahl E., Hess B., Groenhof G., Mark A.E., Berendsen H.J.C. GROMACS: Fast, flexible, and free. J. Comput. Chem. 2005;26:1701–1718. doi: 10.1002/jcc.20291. PubMed DOI

Humphrey W., Dalke A., Schulten K. VMD: Visual molecular dynamics. J. Mol. Graphics. 1996;14:33–38. doi: 10.1016/0263-7855(96)00018-5. PubMed DOI