In pursuit of an efficient solvation approach for the halogen bonded complex between molecular iodine and tetramethylthiourea that reliably reproduces experimental trends, we investigated a range of solvent models, from implicit representations to periodic metadynamics simulations alongside micro-solvation and ONIOM-based methods as robust alternatives. Implicit solvent models fail to describe halogen-bonded complexes in high-polar solvents but provide surprisingly accurate estimates of binding free energies in all low to moderately polar solvents. For accurate and reliable modeling, especially in polar media, explicit solvent representations are essential. Periodic metadynamics simulations typically provide enhanced accuracy in calculating free energy differences, particularly for systems with complex solvation behavior. However, they are computationally demanding and restricted to generalized gradient approximation functionals (GGA). To overcome this limitation and improve accuracy, we employed the machine learning perturbation theory technique, enabling the estimation of free energies at levels of theory beyond the GGA.

Department of Physical and Theoretical Chemistry Faculty of Natural Sciences Comenius University in Bratislava Mlynská dolina Ilkovičova 6 842 15 Bratislava Slovakia

Faculty of Science Palacký University Olomouc 17 Listopadu 1192 12 779 00 Olomouc Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo náměstí 542 2 160 00 Prague Czech Republic

IT4Innovations VŠB Technical University of Ostrava 17 Listopadu 2172 15 708 00 Ostrava Poruba Czech Republic

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Halogen bonding I: Impact on materials chemistry and life sciences, ed. P. Metrangolo and G. Resnati, Springer, Switzerland, 2015

Halogen Bonding, Fundamentals and Applications, ed. P. Metrangolo and G. Resnati, Springer-Verlag, Berlin, Heidelberg, 2008, https://link.springer.com/book/10.1007/978-3-540-74330-9

Politzer P. Lane P. Concha M. C. Ma Y. Murray J. S. J. Mol. Model. 2007;13:305–311. PubMed

Bissantz C. Kuhn B. Stahl M. J. Med. Chem. 2010;53:5061–5084. PubMed PMC

Lu Y. Liu Y. Xu Z. Li H. Liu H. Zhu W. Expert Opin. Drug Discovery. 2012;7:375–383. PubMed

Scholfield M. R. Zanden C. M. V. Carter M. Ho P. S. Protein Sci. 2013;22(2):139–152. PubMed PMC

Gilday L. C. Robinson S. W. Barendt T. A. Langton M. J. Mullaney B. R. Beer P. D. Chem. Rev. 2015;115:7118–7195. PubMed

Cavallo G. Metrangolo P. Milani R. Pilati T. Priimagi A. Resnati G. Terraneo G. Chem. Rev. 2016;116:2478–2601. PubMed PMC

Li B. Zang S.-Q. Wang L.-Y. Mak T. C. W. Coord. Chem. Rev. 2016;308:1–21.

Manna D. Lo R. Vacek J. Miriyala V. M. Bouř P. Wu T. Osifová Z. Nachtigallová D. Dračínský M. Hobza P. Angew. Chem., Int. Ed. 2024;63:e202403218. PubMed

Lo R. Manna D. Vacek J. Bouř P. Wu T. Osifová Z. Socha O. Dračínský M. Hobza P. Angew. Chem., Int. Ed. 2025;64:e202422594. PubMed PMC

Driver M. D. Williamson M. J. Cook J. L. Hunter C. A. Chem. Sci. 2020;11:4456–4466. PubMed PMC

Cook J. L. Hunter C. A. Low C. M. R. Perez-Velasco A. Vinter J. G. Angew. Chem., Int. Ed. 2007;46:3706–3709. PubMed

Aquino A. J. A. Tunega D. Haberhauer G. Gerzabek M. H. Lischka H. J. Phys. Chem. A. 2002;106:1862–1871.

Robertson C. C. Wright J. S. Carrington E. J. Perutz R. N. Hunter C. A. Brammer L. Chem. Sci. 2017;8:5392–5398. PubMed PMC

Hunter C. A. Angew. Chem., Int. Ed. 2004;43:5310–5324. PubMed

Cabot R. Hunter C. A. Chem. Commun. 2009:2005–2007. PubMed

Meredith N. Y. Borsley S. Smolyar I. V. Nichol G. S. Baker C. M. Ling K. B. Cockroft S. L. Angew. Chem., Int. Ed. 2022;61:e202206604. PubMed PMC

Burns R. J. Mati I. K. Muchowska K. B. Adam C. Cockroft S. L. Angew. Chem., Int. Ed. 2020;59:16717–16724. PubMed PMC

Erdélyi M. Chem. Soc. Rev. 2012;41:3547. PubMed

Klaeboe P. J. Am. Chem. Soc. 1967;89:3667–3676.

Sarwar M. G. Dragisic B. Salsberg L. J. Gouliaras C. Taylor M. S. J. Am. Chem. Soc. 2010;132:1646–1653. PubMed

Hawthorne B. Fan-Hagenstein H. Wood E. Smith J. Hanks T. Int. J. Spectrosc. 2013;2013:1–10.

Dumele O. Wu D. Trapp N. Goroff N. Diederich F. Org. Lett. 2014;16:4722–4725. PubMed

Robertson C. C. Perutz R. N. Brammer L. Hunter C. A. Chem. Sci. 2014;5:4179–4183.

Cao J. Yan X. He W. Li X. Li Z. Mo Y. Liu M. Jiang Y.-B. J. Am. Chem. Soc. 2017;139:6605–6610. PubMed

Carlsson A.-C. C., Veiga A. X. and Erdélyi M., Halogen Bonding in Solution, in Halogen Bonding II, ed. P. Metrangolo and G. Resnati, Topics in Current Chemistry, Springer, Cham, 2014, vol. 359, pp. 49–76 PubMed

Lu Y. Li H. Zhu X. Zhu W. Liu H. J. Phys. Chem. A. 2011;115:4467–4475. PubMed

Lu Y. Li H. Zhu X. Liu H. Zhu W. Int. J. Quantum Chem. 2012;112:1421–1430.

Forni A. Rendine S. Pieraccini S. Sironi M. J. Mol. Graphics Modell. 2012;38:31–39. PubMed

Riley K. E. Merz K. M. J. Phys. Chem. A. 2007;111:1688–1694. PubMed

Bauzá A. Quiñonero D. Frontera A. Deyà P. M. Phys. Chem. Chem. Phys. 2011;13:20371. PubMed

Li Q. Li R. Zhou Z. Li W. Cheng J. J. Chem. Phys. 2012;136:014302. PubMed

Li Q.-Z. Jing B. Li R. Liu Z.-B. Li W.-Z. Luan F. Cheng J.-B. Gong B.-A. Sun J.-Z. Phys. Chem. Chem. Phys. 2011;13:2266. PubMed

Klamt A. Schüürmann G. J. Chem. Soc., Perkin Trans. 2. 1993;5:799–805.

Marenich A. V. Cramer C. J. Truhlar D. G. J. Phys. Chem. B. 2009;113:6378–6396. PubMed

Cossi M. Rega N. Scalmani G. Barone V. J. Comput. Chem. 2003;24:669–681. PubMed

Zhang J. Zhang H. Wu T. Wang Q. J. Chem. Theory Comput. 2017;13:1034–1043. PubMed

Grimme S. Antony J. Ehrlich S. Krieg H. J. Chem. Phys. 2010;132:154104. PubMed

Perdew J. P. Ernzerhof M. Burke K. J. Chem. Phys. 1996;105:9982–9985.

Ernzerhof M. Scuseria G. E. J. Chem. Phys. 1999;110:5029–5036.

Adamo C. Barone V. J. Chem. Phys. 1999;110:6158–6170.

Weigend F. Ahlrichs R. Phys. Chem. Chem. Phys. 2005;7:3297. PubMed

Weigend F. Phys. Chem. Chem. Phys. 2006;8:1057. PubMed

Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Petersson G. A., Nakatsuji H., Li X., Caricato M., Marenich A. V., Bloino J., Janesko B. G., Gomperts R., Mennucci B., Hratchian H. P., Ortiz J. V., Izmaylov A. F., Sonnenberg J. L., Williams-Young D., Ding F., Lipparini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T., Ranasinghe D., Zakrzewski V. G., Gao J., Rega N., Zheng G., Liang W., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Throssell K., Montgomery Jr J. A., Peralta J. E., Ogliaro F., Bearpark M. J., Heyd J. J., Brothers E. N., Kudin K. N., Staroverov V. N., Keith T. A., Kobayashi R., Normand J., Raghavachari K., Rendell A. P., Burant J. C., Iyengar S. S., Tomasi J., Cossi M., Millam J. M., Klene M., Adamo C., Cammi R., Ochterski J. W., Martin R. L., Morokuma K., Farkas O., Foresman J. B. and Fox D. J., Gaussian 16 Revision C.01, Gaussian Inc., Wallingford CT, 2016

Mardirossian N. Head-Gordon M. J. Chem. Phys. 2016;144:214110. PubMed

Neese F. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012;2:73–78.

Neese F. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2025;15:e70019.

Grimme S. Chem.–Eur. J. 2012;18:9955–9964. PubMed

Hirshfeld F. L. Theor. Chim. Acta. 1977;44:129–138.

Löwdin P.-O. J. Chem. Phys. 1950;18:365–375.

Löwdin P.-O., On the Nonorthogonality Problem, in Advances in Quantum Chemistry, Elsevier, 1970, vol. 5, pp. 185–199

Sunoj R. B. Anand M. Phys. Chem. Chem. Phys. 2012;14:12715–12736. PubMed

Hadad C. Florez E. Acelas N. Merino G. Restreppo A. Int. J. Quantum Chem. 2019;119:e25766.

Simm G. N. Türtscher P. L. Reiher M. J. Comput. Chem. 2020;41:1144–1145. PubMed

Basdogan Y. Groenenboom M. C. Henderson E. De S. Rempe S. B. Keith J. A. J. Chem. Theory Comput. 2020;16:633–642. PubMed

Svensson M. Humbel S. Froese R. D. J. Matsubara T. Sieber S. Morokuma K. J. Phys. Chem. 1996;100:19357–19363.

Stewart J. J. P. J. Mol. Model. 2013;19:1–32. PubMed PMC

Schneider J. Hamaekers J. Chill S. T. Smidstrup S. Bulin J. Thesen R. Blom A. Stokbro K. Model. Simul. Mater. Sci. Eng. 2017;25:085007.

Smidstrup S. Markussen T. Vancraeyveld P. Wellendorff J. Schneider J. Gunst T. Verstichel B. Stradi D. Khomyakov P. A. Vej-Hansen U. G. Lee M.-E. Chill S. T. Rasmussen F. Penazzi G. Corsetti F. Ojanperä A. Jensen K. Palsgaard M. L. N. Martinez U. Blom A. Brandbyge M. Stokbro K. J. Phys.: Condens. Matter. 2020;32:015901. PubMed

Martyna G. J. Tobias D. J. Klein M. L. J. Chem. Phys. 1994;101:4177–4189.

Kresse G. Hafner J. Phys. Rev. B: Condens. Matter Mater. Phys. 1993;47:558–561. PubMed

Kresse G. Furthmüller J. Comput. Mater. Sci. 1996;6:15–50.

Kresse G. Furthmüller J. Phys. Rev. B: Condens. Matter Mater. Phys. 1996;54:11169–11186. PubMed

Parrinello M. Rahman A. Phys. Rev. Lett. 1980;45:1196–1199.

Parrinello M. Rahman A. J. Appl. Phys. 1981;52:7182–7190.

Nosé S. J. Chem. Phys. 1984;81:511–519.

Nosé S. Prog. Theor. Phys. Suppl. 1991;103:1–46.

Hoover W. G. Phys. Rev. A: At., Mol., Opt. Phys. 1985;31:1695–1697. PubMed

Frenkel D. and Smit B., Understanding Molecular Simulation: From Algorithms to Applications, Computational science series, Academic Press, San Diego, 2nd edn, 2002

Perdew J. P. Burke K. Ernzerhof M. Phys. Rev. Lett. 1996;77:3865–3868. PubMed

Grimme S. Ehrlich S. Goerigk L. J. Comput. Chem. 2011;32:1456–1465. PubMed

Blöchl P. E. Phys. Rev. B: Condens. Matter Mater. Phys. 1994;50:17953–17979. PubMed

Kresse G. Joubert D. Phys. Rev. B: Condens. Matter Mater. Phys. 1999;59:1758–1775.

Schiferl S. K. Wallace D. C. J. Chem. Phys. 1985;83:5203–5209.

Laio A. Parrinello M. Proc. Natl. Acad. Sci. U. S. A. 2002;99:12562–12566. PubMed PMC

Iannuzzi M. Laio A. Parrinello M. Phys. Rev. Lett. 2003;90:238302. PubMed

Flyvbjerg H. Petersen H. J. Chem. Phys. 1989;91:461–466.

Chehaibou B. Badawi M. Bučko T. Bazhirov T. Rocca D. J. Chem. Theory Comput. 2019;15:6333–6342. PubMed

Bučko T. Gešvandtnerová M. Rocca D. J. Chem. Theory Comput. 2020;16:6049–6060. PubMed

Herzog B. Chagas da Silva M. Casier B. Badawi M. Pascale F. Bučko T. Lebègue S. Rocca D. J. Chem. Theory Comput. 2022;18:1382. PubMed

Ramakrishnan R. Dral P. O. Rupp M. von Lilienfeld O. A. J. Chem. Theory Comput. 2015;11:2087–2096. PubMed

Pohorille A. Jarzynski C. Chipot C. J. Phys. Chem. B. 2010;114:10235–10253. PubMed

Perdew J. P. Schmidt K. AIP Conf. Proc. 2001;577:1.

Krukau A. V. Vydrov O. A. Izmaylov A. F. Scuseria G. E. J. Chem. Phys. 2006;125:224106–224111. PubMed

Herzog B. Gallo A. Hummel F. Badawi M. Bučko T. Lebègue S. Grüneis A. Rocca D. npj Comput. Mater. 2024;10:68.

Rey J. Gomez A. Raybaud P. Chizallet C. Bučko T. J. Catal. 2019;373:361–373.

Vrška D. Pitoňák M. Bučko T. J. Chem. Phys. 2024;160:174106. PubMed

Gešvandtnerová M. Rocca D. Bučko T. J. Catal. 2021;396:166.

Chipot C. and Pohorille A., Calculating free energy differences using perturbation theory, in Free Energy Calculations Theory and Applications in Chemistry and Biology, Springer, Berlin, Heidelberg, 2007

Rupp M. Int. J. Quantum Chem. 2015;115:1058–1073.

De S. Bartók A. P. Csányi G. Ceriotti M. Phys. Chem. Chem. Phys. 2016;18:13754. PubMed

Bartók A. P. Kondor R. Csányi G. Phys. Rev. B: Condens. Matter Mater. Phys. 2013;87:184115.

Himanen L. Jäger M. O. Morooka E. V. Federici Canova F. Ranawat Y. S. Gao D. Z. Rinke P. Foster A. S. Comput. Phys. Commun. 2020;247:106949.

Pedregosa F. Varoquaux G. Gramfort A. Michel V. Thirion B. Grisel O. Blondel M. Prettenhofer P. Weiss R. Dubourg V. Vanderplas J. Passos A. Cournapeau D. Brucher M. Perrot M. Duchesnay E. J. Mach. Learn. Res. 2011;12:2825–2830.

Lo R. Mašínová A. Lamanec M. Nachtigallová D. Hobza P. J. Comput. Chem. 2023;44:329. PubMed