[PDF]     https://doi.org/10.3952/physics.2026.66.2.6

Open access article / Atviros prieigos straipsnis
Lith. J. Phys. 66, 113–124 (2026)
 


A COMPUTATIONAL QM/MD 17O NMR STUDY OF TAUTOMERIC EQUILIBRIUM OF MYCOTOXIN CITRININ IN DICHLOROMETHANE SOLUTION
  Žyginta Murnikova and Kęstutis Aidas
Institute of Chemical Physics, Faculty of Physics, Vilnius University, Saulėtekio 3, 10257 Vilnius, Lithuania
Email: kestutis.aidas@ff.vu.lt

Received 2 December 2025; accepted 21 January 2026

The tautomeric equilibrium of citrinin in dichloromethane was investigated using classical molecular dynamics and linear-response QM/MM calculations of 17O NMR shielding constants. MD simulations showed that solvent distribution around the para- and ortho-quinone methide tautomers is essentially uniform, as expected for an isotropic non-hydrogen-bonding solvent of medium polarity. The tautomeric ratio between the p- and o-citrinin forms was optimized to best match experimental and computed relative 17O NMR spectra. The resulting tautomeric ratio of p-to-o-citrinin of 7:4 closely reproduces the experimental value of 4:3, confirming the near-thermodynamic equivalence of the two tautomers, with a slight preference for the para form. A thermodynamic-cycle-based quantum-chemical estimate yielded virtually the same qualitative conclusion. Attempts to include the endiol tautomer of citrinin showed it to be unstable in a dielectric-continuum solvent model; thus, the endiol tautomer is not expected to form in dichloromethane and does not contribute to the observed NMR spectra.
Keywords: citrinin, tautomerism, nuclear magnetic resonance, molecular dynamics simulation, quantum mechanics/molecular mechanics


MIKOTOKSINO CITRININO TAUTOMERINĖ PUSIAUSVYRA DICHLORMETANO TIRPALE: 17O BMR SPEKTRŲ MODELIAVIMAS MOLEKULINĖS DINAMIKOS SIMULIACIJOMIS IR KVANTINĖS MECHANIKOS METODAIS
Žyginta Murnikova, Kęstutis Aidas
Vilniaus universiteto Fizikos fakulteto Cheminės fizikos institutas, Vilnius, Lietuva
 
Modeliuota mikotoksino citrinino tautomerinė pusiausvyra dichlormetano tirpale naudojant klasikines molekulių dinamikos (MD) simuliacijas bei 17O branduolių magnetinio rezonanso (BMR) ekranavimo konstantų skaičiavimus. MD simuliacijos atskleidė, kad dichlormetano tirpiklio molekulių pasiskirstymas aplink para- ar orto-chinono metido citrinino tautomerus yra mažai struktūrizuotas, ko ir galima tikėtis atsižvelgiant į tai, kad dichlormetanas yra vidutinio poliškumo, vandenilinių ryšių suformuoti negalintis tirpiklis. Naudojant jungtinius kvantinės mechanikos ir molekulinės mechanikos metodus buvo apskaičiuotos p- ir o-citrinino tautomerų 17O BMR ekranavimo konstantos dichlormetano tirpale. Remiantis šių skaičiavimų rezultatais, buvo sumodeliuotas suvidurkintas citrinino 17O BMR spektras, kuris su eksperimentiniu spektru sutapo geriausiai tada, kai pusiausvirasis p- ir o-citrinino tautomerų santykis buvo lygus 7:4. Šis apskaičiuotas santykis labai gerai sutapo su nustatytu eksperimentiškai, lygiu 4:3. Tai rodo, kad abu citrinino tautomerai yra praktiškai energetiškai lygiaverčiai dichlormetano tirpale, pusiausvyrai mažumėlę pasislinkus į para-chinono metido tautomero pusę. Darbe taip pat buvo bandoma įvertinti endiolio tautomero įtaką citrinino 17O BMR spektrui. Vis dėlto šis tautomeras nėra stabilus dichlormetano tirpiklyje, kai modeliuojama dielektrinio kontinuumo metodu. Tikėtina, kad citrinino endiolio tautomeras dichlormetano tirpale nesiformuoja ir neturi įtakos jo BMR spektrams.


References / Nuorodos

[1] A. Lesage, Recent advances in solid-state NMR spectroscopy of spin I = 1/2 nuclei, Phys. Chem. Chem. Phys. 11, 6876 (2009),
https://doi.org/10.1039/b907733m
[2] O. Pecher, J. Carretero-Gonzalez, K.J. Griffith, and C.P. Grey, Materials' methods: NMR in battery research, Chem. Mater. 29, 213 (2016),
https://doi.org/10.1021/acs.chemmater.6b03183
[3] B. Reif, S.E. Ashbrook, L. Emsley, and M. Hong, Solid-state NMR spectroscopy, Nat. Rev. Methods Primers 1, 1 (2021),
https://doi.org/10.1038/s43586-020-00002-1
[4] S. Ahlawat, K.R. Mote, N. Lakomek, and V. Agarwal, Solid-state NMR: methods for biological solids, Chem. Rev. 122, 9643 (2022),
https://doi.org/10.1021/acs.chemrev.1c00852
[5] M. Renault, A. Cukkemane, and M. Baldus, Solid-state NMR spectroscopy on complex biomolecules, Angew. Chem., Int. Ed. 49, 8346 (2010),
https://doi.org/10.1002/anie.201002823
[6] J. Keeler. Understanding NMR Spectroscopy, 2nd ed. (Wiley, Chichester, 2010),
https://www.wiley.com/en-us/Understanding+NMR+Spectroscopy%2C+2nd+Edition-p-9780470746080
[7] R.M. Claramunt, C. López, M.D. Santa María, D. Sanz, and J. Elguero, The use of NMR spectroscopy to study tautomerism, Prog. Nucl. Magn. Reson. Spectrosc. 49, 169 (2006),
https://doi.org/10.1016/j.pnmrs.2006.07.001
[8] G. Gocheva, N. Petkov, A. Garcia Luri, S. Iliev, N. Ivanova, J. Petrova, Y. Mitrev, G. Madjarova, and A. Ivanova, Tautomerism in folic acid: Combined molecular modelling and NMR study, J. Mol. Liq. 292, 111392 (2019),
https://doi.org/10.1016/j.molliq.2019.111392
[9] K. Bártová, I. Císařová, A. Lyčka, and M. Dračínský, Tautomerism of azo dyes in the solid state studied by 15N, 14N, 13C and 1H NMR spectroscopy, X-ray diffraction and quantum-chemical calculations, Dye. Pigment. 178, 108342 (2020),
https://doi.org/10.1016/j.dyepig.2020.108342
[10] A.C.F. de Albuquerque, G.S. Corrêa, G.T. Albuquerque, F.L.P. Costa, L.T. Costa, M.R. Lage, J.W. de M. Carneiro, and F.M. dos S. Junior, Theoretical study of keto-enol tautomerism in 7-epi-clusianone by quantum chemical calculations of NMR chemical shifts, J. Mol. Model. 28, 239 (2022),
https://doi.org/10.1007/s00894-022-05234-4
[11] K. Aidas, K.V. Mikkelsen, and J. Kongsted, On the existence of the H3 tautomer of adenine in aqueous solution. Rationalizations based on hybrid quantum mechanics/molecular mechanics predictions, Phys. Chem. Chem. Phys. 12, 761 (2010),
https://doi.org/10.1039/B915604F
[12] J. Tomasi and M. Persico, Molecular interactions in solution: An overview of methods based on continuous distributions of the solvent, Chem. Rev. 94, 2027 (1994),
https://doi.org/10.1021/cr00031a013
[13] J. Tomasi, B. Mennucci, and R. Cammi, Quantum mechanical continuum solvation models, Chem. Rev. 105, 2999 (2005),
https://doi.org/10.1021/cr9904009
[14] A. Klamt and G. Schüürmann, COSMO: A new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient, J. Chem. Soc. Perkin Trans. 2, 799 (1993),
https://doi.org/10.1039/P29930000799
[15] K. Kitaura and K. Morokuma, A new energy decomposition scheme for molecular interactions within the Hartree-Fock approximation, Int. J. Quantum Chem. 10, 325 (1976),
https://doi.org/10.1002/qua.560100211
[16] A. Warshel and M. Levitt, Theoretical studies of enzymic reactions: Dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme, J. Mol. Biol. 103, 227 (1976),
https://doi.org/10.1016/0022-2836(76)90311-9
[17] J. Kongsted, A. Osted, K.V. Mikkelsen, and O. Christiansen, The QM/MM approach for wavefunctions, energies and response functions within self-consistent field and coupled cluster theories, Mol. Phys. 100, 1813 (2002),
https://doi.org/10.1080/00268970110117106
[18] J.M. Olsen, K. Aidas, and J. Kongsted, Excited states in solution through polarizable embedding, J. Chem. Theory Comput. 6, 3721 (2010),
https://doi.org/10.1021/ct1003803
[19] H.C. Georg, K. Coutinho, and S. Canuto, Converged electronic polarization of acetone in liquid water and the role in the n–π transition, Chem. Phys. Lett. 429, 119 (2006),
https://doi.org/10.1016/j.cplett.2006.08.047
[20] N. Arul Murugan, J. Kongsted, Z. Rinkevicius, and H. Ågren, Breakdown of the first hyperpolarizability/bond-length alternation parameter relationship, Proc. Natl. Acad. Sci. USA. 107, 16453 (2010),
https://doi.org/10.1073/pnas.1006572107
[21] C.B. Nielsen, O. Christiansen, K.V. Mikkelsen, and J. Kongsted, Density functional self-consistent quantum mechanics/molecular mechanics theory for linear and nonlinear molecular properties: Applications to solvated water and formaldehyde, J. Chem. Phys. 126, 154112 (2007),
https://doi.org/10.1063/1.2711182
[22] T. Schwabe, J.M. Haugaard Olsen, K. Sneskov, J. Kongsted, and O. Christiansen, Solvation effects on electronic transitions: Exploring the performance of advanced solvent potentials in polarizable embedding calculations, J. Chem. Theory Comput. 7, 2209 (2011),
https://doi.org/10.1021/ct200258g
[23] K. Aidas, A. Møgelhøj, H. Kjær, C.B. Nielsen, K.V. Mikkelsen, K. Ruud, O. Christiansen, and J. Kongsted, Solvent effects on NMR isotropic shielding constants. A comparison between explicit polarizable discrete and continuum approaches, J. Phys. Chem. A. 111, 4199 (2007),
https://doi.org/10.1021/jp068693e
[24] D. Lengvinaitė, K. Aidas, and L. Kimtys, Molecular aggregation in liquid acetic acid: insight fromolecular dynamics/quantum mechanics modelling of structural and NMR properties, Phys. Chem. Chem. Phys. 21, 14811 (2019),
https://doi.org/10.1039/C9CP01892A
[25] E. Sipavičius, L. Mikalauskas, V. Klimavicius, and K. Aidas, Intermolecular organization in aqueous mixtures of choline lysinate studied via NMR and molecular dynamics/quantum mechanics, Phys. Chem. Chem. Phys. 27, 14790 (2025),
https://doi.org/10.1039/D5CP00861A
[26] D. Lengvinaitė, V. Klimavičius, V. Balevicius, and K. Aidas, Computational NMR study of ion pairing of 1-decyl-3-methylimidazolium chloride in molecular solvents, J. Phys. Chem. B 124, 10776 (2020),
https://doi.org/10.1021/acs.jpcb.0c07450
[27] J.W.G. de Oliveira Filho, M.T. Islam, E.S. Ali, S.J. Uddin, J.V. de Oliveira Santos, M.V. Oliveira Barros de Alencar, A.L. Gomes Júnior, M.F. Correia Jardim Paz, M.d.R.M. de Brito, J.M. de Castro e Sousa, et al., A comprehensive review on biological properties of citrinin, Food Chem. Toxicol. 110, 130 (2017),
https://doi.org/10.1016/j.fct.2017.10.002
[28] A.M. Ambrose, Some toxicological and pharmacological properties of citrinin, J. Pharmacol. Exp. Ther. 88, 173 (1946),
https://doi.org/10.1016/S0022-3565(25)05913-0
[29] C.H. Chang, F.Y. Yu, L.T. Wang, Y.S. Lin, and B.H. Liu, Activation of ERK and JNK signaling pathways by mycotoxin citrinin in human cells, Toxicol. Appl. Pharmacol. 237, 281 (2009),
https://doi.org/10.1016/j.taap.2009.03.021
[30] Y. Nakajima, H. Iguchi, S. Kamisuki, F. Sugawara, T. Furuichi, and Y. Shinoda, Low doses of the mycotoxin citrinin protect cortical neurons against glutamate-induced excitotoxicity, J. Toxicol. Sci. 41, 311 (2016),
https://doi.org/10.2131/jts.41.311
[31] A.-A.P. de Menezes, R.P.S. Aguiar, J.O. Santos, C. Sarkar, M.T. Islam, A.L. Braga, M.M. Hasan, F.C.C. da Silva, J. Sharifi-Rad, A. Dey, D. Calina, A.A.C. Melo-Cavalcante, and J.M.C. Sousa, Citrinin as a potential anti-cancer therapy: A comprehensive review, Chem. Biol. Interact. 381, 110561 (2023),
https://doi.org/10.1016/j.cbi.2023.110561
[32] N. Atar, M.L. Yola, and T. Eren, Sensitive determination of citrinin based on molecular imprinted electrochemical sensor, Appl. Surf. Sci. 362, 315 (2016),
https://doi.org/10.1016/j.apsusc.2015.11.222
[33] G.H. Degen, N. Ali, and U. Gundert-Remy, Preliminary data on citrinin kinetics in humans and their use to estimate citrinin exposure based on biomarkers, Toxicol. Lett. 282, 43 (2018),
https://doi.org/10.1016/j.toxlet.2017.10.006
[34] D. Abramson, R. Hulasare, R.K. York, N.D.G. White, and D.S. Jayas, Mycotoxins, ergosterol, and odor volatiles in durum wheat during granary storage at 16% and 20% moisture content, J. Stored Prod. Res. 41, 67 (2005),
https://doi.org/10.1016/j.jspr.2003.11.002
[35] EFSA Panel on Contaminants in the Food Chain (CONTAM), Scientific opinion on the risks for public and animal health related to the presence of citrinin in food and feed, EFSA J. 10, 2605 (2012),
https://doi.org/10.2903/j.efsa.2012.2605
[36] U. Sankawa, Y. Ebizuka, H. Noguchi, Y. Isikawa, S. Kitaghawa, Y. Yamamoto, T. Kobayashi, Y. Iitak, and H. Seto, Biosynthesis of citrinin in aspergillus terreus: Incorporation studies with [2-13C, 2-2H3], [1-13C, 18O2] and [1-13C, 17O]-acetate, Tetrahedron 39, 3583 (1983),
https://doi.org/10.1016/S0040-4020(01)88669-5
[37] R. Poupko, Z. Luz, and R. Destro, Carbon-13 NMR of citrinin in the solid state and in solutions, J. Phys. Chem. A 101, 5097 (1997),
https://doi.org/10.1021/jp970681t
[38] M.H. Lauer, M.H. Gehlen, K. de Jesus, and R.G.S. Berlinck, Fluorescence spectroscopy and confocal microscopy of the mycotoxin citrinin in condensed phase and hydrogel films, J. Fluoresc. 24, 745 (2014),
https://doi.org/10.1007/s10895-013-1347-y
[39] R. Destro and R.E. Marsh, Temperature dependence of tautomeric equilibria in the solid state: The case of citrinin, J. Am. Chem. Soc. 106, 7269 (1984),
https://doi.org/10.1021/ja00335a082
[40] R. Destro, Proton transfer in the solid state: Therymodynamic parameters from an X-ray study in the temperature range 20–293 K, Chem. Phys. Lett. 181, 232 (1991),
https://doi.org/10.1016/0009-2614(91)90359-H
[41] J. Barber, J.L. Cornford, T.D. Howard, and D. Sharples, The structure of citrinin in vivo, J. Chem. Soc. Perkin Trans. 1987(0), 2743 (1987),
https://doi.org/10.1039/p19870002743
[42] M. Appell, D. Moravec, and W.B. Bosma, Quantum chemical study of the structure and properties of citrinin, Mol. Simulat. 38, 284 (2012),
https://doi.org/10.1080/08927022.2011.619984
[43] P.V. Bharatam, O.R. Valanju, A.A. Wani, and D.K. Dhaked, Importance of tautomerism in drugs, Drug Discov. Today 28, 103494 (2023),
https://doi.org/10.1016/j.drudis.2023.103494
[44] A.D. Becke, Density-functional thermochemistry. III. The role of exact exchange, J. Chem. Phys. 98, 5648 (1993),
https://doi.org/10.1063/1.464913
[45] R.A. Kendall, T.H. Dunning, and R.J. Harrison, Electron affinities of the first-row atoms revisited. Systematic basis sets and wave functions, J. Chem. Phys. 96, 6796 (1992),
https://doi.org/10.1063/1.462569
[46] V. Barone, M. Cossi, and J. Tomasi, Geometry optimization of molecular structures in solution by the polarizable continuum model, J. Comput. Chem. 19, 404 (1998),
https://doi.org/10.1002/(SICI)1096-987X(199803)19:4<404::AID-JCC3>3.3.CO;2-L
[47] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalmani, V. Barone, G.A. Petersson, H. Nakatsuji, et al., Gaussian 16, Revision C.01 (Gaussian Inc., Wallingford, CT, 2026),
https://gaussian.com/gaussian16/
[48] C.M. Breneman and K.B. Wiberg, Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in formamide conformational analysis, J. Comp. Chem. 11, 361 (1990),
https://doi.org/10.1002/jcc.540110311
[49] W.L. Jorgensen, D.S. Maxwell, and J. Tirado-Rives, Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids, J. Am. Chem. Soc. 118, 11225 (1996),
https://doi.org/10.1021/JA9621760
[50] D. Lim, W.L. Jorgensen, D.A. Hrovat, and W.T. Borden, Solvent effects on the ring opening of cyclopropanones to oxyallyls: A combined ab initio and Monte Carlo study, J. Am. Chem. Soc. 116, 3494 (1994),
https://doi.org/10.1021/ja00087a040
[51] J. Reščič and P. Linse, MOLSIM: A modular molecular simulation software, J. Comp. Chem. 36, 1259 (2015),
https://doi.org/10.1002/jcc.23919
[52] L. Verlet, Computer 'experiments' on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules, Phys. Rev. 159, 98 (1967),
https://doi.org/10.1103/PhysRev.159.98
[53] H.J.C. Berendsen, J.P.M. Postma, W.F. van Gunsteren, A. DiNola, and J.R. Haak, Molecular dynamics with coupling to an external bath, J. Chem. Phys. 81, 3684 (1984),
https://doi.org/10.1063/1.448118
[54] J. Kongsted, C.B. Nielsen, K.V. Mikkelsen, O. Christiansen, and K. Ruud, Nuclear magnetic shielding constants of liquid water: Insights from hybrid quantum mechanics/molecular mechanics models, J. Chem. Phys. 126, 034510 (2007),
https://doi.org/10.1063/1.2424713
[55] K. Aidas, C. Angeli, K.L. Bak, V. Bakken, R. Bast, L. Boman, O. Christiansen, R. Cimiraglia, S. Coriani, P. Dahle, et al., The Dalton quantum chemistry program system, WIREs Comput. Mol. Sci. 4, 269 (2014),
https://doi.org/10.1002/wcms.1172
[56] C. Adamo and V. Barone, Toward reliable density functional methods without adjustable parameters: The PBE0 model, J. Chem. Phys. 110, 6158 (1999),
https://doi.org/10.1063/1.478522
[57] F. Weigend and R. Ahlrichs, Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy, Phys. Chem. Chem. Phys. 7, 3297 (2005),
https://doi.org/10.1039/b508541a
[58] L. Gagliardi, R. Lindh, and G. Karlström, Local properties of quantum chemical systems: The LoProp approach, J. Chem. Phys. 121, 4494 (2004),
https://doi.org/10.1063/1.1778131
[59] A. Cedillo, S. Kvedaravičiūtė, and K. Aidas, Prediction of the tautomer stability and acidity of phenacylpyridines in aqueous solution, Theor. Chem. Acc. 139, 52 (2020),
https://doi.org/10.1007/s00214-020-2558-3
[60] Y.C. Martin, Let's not forget tautomers, J. Comput. Aided Mol. Des. 23, 693 (2009),
https://doi.org/10.1007/s10822-009-9303-2
[61] Ž. Murnikova, V. Klimavicius, F. Mocci, A. Laaksonen, and K. Aidas, On the mechanism behind the enhanced solubility of glibenclamide in aqueous ionic liquid solution, J. Mol. Liq. 422, 127153 (2025),
https://doi.org/10.1016/j.molliq.2025.127153
[62] Y. Zhao, N.E. Schultz, and D.G. Truhlar, Density functional for spectroscopy: No long-range selfinteraction error, good performance for Rydberg and charge-transfer states, and better performance on average than B3LYP for ground states, J. Chem. Theory Comput. 2, 364(2006),
https://doi.org/10.1021/jp066479k
[63] A.V. Marenich, C.J. Cramer, and D.G. Truhlar, Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions, J. Phys. Chem. B 113, 6378 (2009),
https://doi.org/10.1021/jp810292n
[64] R.F. Ribeiro, A.V. Marenich, C.J. Cramer, and D.G. Truhlar, Prediction of SAMPL2 aqueous solvation free energies and tautomeric ratios using the SM8, SM8AD, and SMD solvation models, J. Comput. Aided Mol. Des. 24, 317 (2010),
https://doi.org/10.1007/s10822-010-9333-9
[65] J.J. Eriksen, J.M.H. Olsen, K. Aidas, H. Ågren, K.V. Mikkelsen, and J. Kongsted, Computational protocols for prediction of solute NMR relative chemical shifts. A case study of L-tryptophan in aqueous solution, J. Comp. Chem. 32, 2853 (2011),
https://doi.org/10.1002/jcc.21867