Computational insights into PFOS and PFOA encapsulation within a covalent "cage-of-cages" architecture
Mechanistic Insights into PFAS Binding, Confinement, and Desorption
DOI:
https://doi.org/10.20450/mjcce.2026.3405Keywords:
Molecular Cage, PFAS, Density Functional Theory, Nudged Elastic Band, QTAIMAbstract
The widespread contamination of water by per- and polyfluoroalkyl substances (PFAS) demands the development of efficient and selective removal strategies. In this study, we use computational methods to investigate the potential of a covalently bonded "cage-of-cages" molecular architecture for PFAS sequestration, employing density functional theory (DFT), molecular dynamics (MD), nudged elastic band (NEB) calculations, and noncovalent interaction (NCI) analyses. DFT calculations show stronger binding of perfluorooctanesulfonic acid (PFOS) (–33.07 kcal/mol) relative to perfluorooctanoic acid (PFOA) (−24.63 kcal/mol), primarily driven by van der Waals and electrostatic interactions within the confined cage interior. MD simulations confirm the stable confinement of both PFAS molecules in water, while NEB calculations reveal a higher relative desorption energy barrier for PFOS (109.18 kcal/mol) compared with PFOA (99.84 kcal/mol), implying stronger retention of PFOS within the cage cavity. Collectively, these findings demonstrate that hierarchical molecular cages served as promising supramolecular platforms for PFAS sequestration, offering a mechanistic computational basis for future experimental validation and rational adsorbent design.
References
(1) Zhang, L.; Jin, Y.; Tao, G.-H.; Gong, Y.; Hu, Y.; He, L.; Zhang, W. Desymmetrized Vertex Design Toward a Molecular Cage With Unusual Topology. Angew. Chemie 2020. https://doi.org/10.1002/ange.202007454
(2) Montà-González, G.; Sancenón, F.; Martínez-Máñez, R.; Martí-Centelles, V. Purely Covalent Molecular Cages and Containers for Guest Encapsulation. Chem. Rev. 2022, 122 (16), 13636–13708.
https://doi.org/10.1021/acs.chemrev.2c00198
(3) Dutta, S. Synthesis and Applications of Cage-Based Covalent Organic Frameworks. Cryst. Growth & Des. 2024. https://doi.org/10.1021/acs.cgd.4c00701
(4) Deegan, M. M.; Bhattacharjee, R.; Caratzoulas, S.; Bloch, E. D. Stabilizing Porosity in Organic Cages Through Coordination Chemistry. Inorg. Chem. 2021. https://doi.org/10.1021/acs.inorgchem.0c03590
(5) Moneypenny, T. P.; Walter, N. P.; Cai, Z.; Miao, Y.; Gray, D. L.; Hinman, J. J.; Lee, S.; Zhang, Y.; Moore, J. S. Impact of Shape Persistence on the Porosity of Molecular Cages. J. Am. Chem. Soc. 2017.
https://doi.org/10.1021/jacs.7b00189
(6) Wang, C.; Tian, L.; Wang, Z.; Wang, S.; Gao, N.; Zhou, K.; Yin, X.; Zhang, W.; Zhao, L.; Li, G. Molecular Cage-Bridged Plasmonic Structures With Well-Defined Nanogaps as Well as the Capability of Reversible and Selective Guest Trapping. Chem. Sci. 2018.
https://doi.org/10.1039/c7sc03536e
(7) Huang, F. Q.; Ma, L.; Che, Y.; Jiang, H.; Chen, X.; Wang, Y. Corannulene-Based Coordination Cage With Helical Bias. J. Org. Chem. 2018.
https://doi.org/10.1021/acs.joc.7b02709
(8) Zou, D.; Li, Z.; Long, D.; Dong, X.; Qu, H.; Yang, L.; Cao, X. Molecular Cage With Dual Outputs of Photochromism and Luminescence Both in Solution and the Solid State. Acs Appl. Mater. & Interfaces 2023. https://doi.org/10.1021/acsami.2c23196
(9) Takezawa, H.; Tabuchi, R.; Sunohara, H.; Fujita, M. Confinement of Water-Soluble Cationic Substrates in a Cationic Molecular Cage by Capping the Portals With Tripodal Anions. J. Am. Chem. Soc. 2020.
https://doi.org/10.1021/jacs.0c08835
(10) Das, S.; Ronen, A. A Review on Removal and Destruction of Per- And Polyfluoroalkyl Substances (PFAS) by Novel Membranes. Membranes (Basel). 2022. https://doi.org/10.3390/membranes12070662
(11) He, Y. Fluorinated Nonporous Adaptive Cages for the Efficient Removal of Perfluorooctanoic Acid From Aqueous Source Phases. J. Am. Chem. Soc. 2024.
https://doi.org/10.1021/jacs.3c14213
(12) Kim, J. Evaluation of a Porous Membrane as a Mass-Transfer Efficient Structure for the Adsorption of Per- And Polyfluoroalkyl Substances From Drinking Water. Acs Es&t Eng. 2024.
https://doi.org/10.1021/acsestengg.3c00515
(13) Tan, X.; Dewapriya, P.; Prasad, P.; Chang, Y.; Huang, X.; Wang, Y.; Gong, X.; Hopkins, T. E.; Fu, C.; Thomas, K. V; Pеng, H.; Whittaker, A. K.; Zhang, C. Efficient Removal of Perfluorinated Chemicals From Contaminated Water Sources Using Magnetic Fluorinated Polymer Sorbents. Angew. Chemie 2022.
https://doi.org/10.1002/anie.202213071
(14) Chaudhary, M. Efficient PFOA Removal From Drinking Water by a Dual-Functional Mixed-Matrix-Composite Nanofiltration Membrane. NPJ Clean Water 2023. https://doi.org/10.1038/s41545-023-00286-2
(15) Camdzic, D. Rapid Capture of Per- And Polyfluoroalkyl Substances Using a Self-Assembling Zirconium-Based Metal-Organic Cage. Acs Appl. Eng. Mater. 2023. https://doi.org/10.1021/acsaenm.3c00592
(16) Chaleshtari, Z. A.; Foudazi, R. A Review on Per- And Polyfluoroalkyl Substances (PFAS) Remediation: Separation Mechanisms and Molecular Interactions. Acs Es&t Water 2022.
https://doi.org/10.1021/acsestwater.2c00271
(17) Zeng, C.; Atkinson, A. J.; Sharma, N.; Ashani, H.; Hjelmstad, A.; Venkatesh, K.; Westerhoff, P. Removing Per‐ and Polyfluoroalkyl Substances From Groundwaters Using Activated Carbon and Ion Exchange Resin Packed Columns. Awwa Water Sci. 2020.
https://doi.org/10.1002/aws2.1172
(18) Li, R.; Alomari, S.; İslamoğlu, T.; Farha, O. K.; Fernando, S.; Thagard, S. M.; Holsen, T. M.; Wriedt, M. Systematic Study on the Removal of Per- And Polyfluoroalkyl Substances From Contaminated Groundwater Using Metal–Organic Frameworks. Environ. Sci. & Technol. 2021.
https://doi.org/10.1021/acs.est.1c03974
(19) Barpaga, D.; Zheng, J.; Han, K. S.; Soltis, J. A.; Shutthanandan, V.; Basuray, S.; McGrail, B. P.; Chatterjee, S.; Motkuri, R. K. Probing the Sorption of Perfluorooctanesulfonate Using Mesoporous Metal–Organic Frameworks From Aqueous Solutions. Inorg. Chem. 2019.
https://doi.org/10.1021/acs.inorgchem.9b00380
(20) Xiao, L.; Ching, C.; Ling, Y.; Nasiri, M.; Klemes, M. J.; Reineke, T. M.; Helbling, D. E.; Dichtel, W. R. Cross-Linker Chemistry Determines the Uptake Potential of Perfluorinated Alkyl Substances by Β-Cyclodextrin Polymers. Macromolecules 2019.
https://doi.org/10.1021/acs.macromol.9b00417
(21) Choudhary, A.; Dong, D.; Tsianou, M.; Alexandridis, P.; Bedrov, D. Adsorption Mechanism of Perfluorooctanoate on Cyclodextrin-Based Polymers: Probing the Synergy of Electrostatic and Hydrophobic Interactions With Molecular Dynamics Simulations. Acs Mater. Lett. 2022.
https://doi.org/10.1021/acsmaterialslett.2c00168
(22) Dickman, R. A.; Aga, D. S. A Review of Recent Studies on Toxicity, Sequestration, and Degradation of per- and Polyfluoroalkyl Substances (PFAS). J. Hazard. Mater. 2022, 436, 129120.
https://doi.org/10.1016/J.JHAZMAT.2022.129120
(23) Zhu, Q.; Qu, H.; Avci, G.; Hafizi, R.; Zhao, C.; Day, G. M.; Jelfs, K. E.; Little, M. A.; Cooper, A. I. Computationally Guided Synthesis of a Hierarchical [4[2+3]+6] Porous Organic ‘Cage of Cages.’ Nat. Synth. 2024 2024, 1–10.
https://doi.org/10.1038/s44160-024-00531-7
(24) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. urn:issn:2052-5206 2016, 72 (2), 171–179.
https://doi.org/10.1107/S2052520616003954
(25) Maglic, J. B.; Lavendomme, R. MoloVol: An Easy-to-Use Program for Analyzing Cavities, Volumes and Surface Areas of Chemical Structures. J. Appl. Crystallogr. 2022, 55 (Pt 4), 1033–1044.
https://doi.org/10.1107/S1600576722004988/YR5079SUP1.PDF
(26) Meng, E. C.; Goddard, T. D.; Pettersen, E. F.; Couch, G. S.; Pearson, Z. J.; Morris, J. H.; Ferrin, T. E. UCSF ChimeraX: Tools for Structure Building and Analysis. Protein Sci. 2023, 32 (11), e4792.
https://doi.org/10.1002/PRO.4792
(27) Neese, F. Software Update: The ORCA Program System—Version 5.0. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2022, e1606.
https://doi.org/10.1002/WCMS.1606
(28) Neese, F. Software Update: The ORCA Program System, Version 4.0. WIREs Comput. Mol. Sci. 2018, 8 (1), e1327. https://doi.org/10.1002/wcms.1327
(29) Neese, F.; Wennmohs, F.; Becker, U.; Riplinger, C. The ORCA Quantum Chemistry Program Package. J. Chem. Phys. 2020, 152 (22), 224108.
https://doi.org/10.1063/5.0004608/1061982
(30) Mardirossian, N.; Head-Gordon, M. ΩB97M-V: A Combinatorially Optimized, Range-Separated Hybrid, Meta-GGA Density Functional with VV10 Nonlocal Correlation. J. Chem. Phys. 2016, 144 (21).
https://doi.org/10.1063/1.4952647
(31) Caldeweyher, E.; Mewes, J. M.; Ehlert, S.; Grimme, S. Extension and Evaluation of the D4 London-Dispersion Model for Periodic Systems. Phys. Chem. Chem. Phys. 2020, 22 (16), 8499–8512.
https://doi.org/10.1039/D0CP00502A
(32) Laun, J.; Vilela Oliveira, D.; Bredow, T. Consistent Gaussian Basis Sets of Double- and Triple-Zeta Valence with Polarization Quality of the Fifth Period for Solid-State Calculations. J. Comput. Chem. 2018, 39 (19), 1285–1290. https://doi.org/10.1002/JCC.25195
(33) Garcia-Ratés, M.; Neese, F. Effect of the Solute Cavity on the Solvation Energy and Its Derivatives within the Framework of the Gaussian Charge Scheme. J. Comput. Chem. 2020, 41 (9), 922–939.
https://doi.org/10.1002/JCC.26139
(34) Barone, V.; Cossi, M. Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J. Phys. Chem. A 1998, 102 (11), 1995–2001. https://doi.org/10.1021/JP9716997
(35) Neese, F. The SHARK Integral Generation and Digestion System. J. Comput. Chem. 2023, 44 (3), 381–396. https://doi.org/10.1002/JCC.26942
(36) Lu, T.; Chen, F. Multiwfn: A Multifunctional Wave-function Analyzer. J. Comput. Chem. 2012, 33 (5), 580–592. https://doi.org/10.1002/jcc.22885
(37) Berisha, A. Unraveling the Electronic Influence and Nature of Covalent Bonding of Aryl and Alkyl Radicals on the B12N12 Nanocage Cluster. Sci. Reports 2023 131 2023, 13 (1), 1–11.
https://doi.org/10.1038/s41598-023-28055-8
(38) Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual Molecular Dynamics. J. Mol. Graph. 1996, 14 (1), 33–38. https://doi.org/10.1016/0263-7855(96)00018-5
(39) Berisha, A. Interactions between the Aryldiazonium Cations and Graphene Oxide: A DFT Study. J. Chem. 2019, 2019. https://doi.org/10.1155/2019/5126071
(40) Akkermans, R. L. C.; Spenley, N. A.; Robertson, S. H. COMPASS III: Automated Fitting Workflows and Extension to Ionic Liquids. 2020, 47 (7), 540–551.
https://doi.org/10.1080/08927022.2020.1808215
(41) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chem. – A Eur. J. 2012, 18 (32), 9955–9964.
https://doi.org/10.1002/CHEM.201200497
(42) Marom, N.; Tkatchenko, A.; Rossi, M.; Gobre, V. V.; Hod, O.; Scheffler, M.; Kronik, L. Dispersion Interactions with Density-Functional Theory: Benchmarking Semiempirical and Interatomic Pairwise Corrected Density Functionals. J. Chem. Theory Comput. 2011, 7 (12), 3944–3951.
https://doi.org/10.1021/CT2005616
(43) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132 (18), 6498–6506.
https://doi.org/10.1021/JA100936W/SUPPL_FILE/JA100936W_SI_002.PDF
(44) Berisha, A. First Principles Details into the Grafting of Aryl Radicals onto the Free-Standing and Borophene/ Ag(1 1 1) Surfaces. Chem. Phys. 2021, 544, 111124. https://doi.org/10.1016/j.chemphys.2021.111124
(45) Eyupoglu, V.; Akin, M. B.; Kaya, S.; Çaylak, O.; Berisha, A.; Çetinkaya, S. Effective Removal of Methylene Blue Dye from Aqueous Solution Using Macrolepiota Procera Mushroom: Experimental and Theoretical Studies. J. Mol. Liq. 2025, 418.
https://doi.org/10.1016/j.molliq.2024.126714
(46) Gürer, E. S.; Yıldırım, Ş.; Kocyigit, Ü. M.; Berisha, A.; Kaya, S. Experimental, Density Functional Theory, Molecular Docking and ADMET Analyses on the Role of Different Plant Extracts of Aronia Melanocarpa (Michx) Elliot Species on Acetylcholinesterase Enzyme Activity. J. Mol. Struct. 2025, 1321, 139893.
https://doi.org/10.1016/J.MOLSTRUC.2024.139893
(47) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Towards Quantitative Analysis of Intermolecular Interactions with Hirshfeld Surfaces. Chem. Commun. 2007, No. 37, 3814–3816.
https://doi.org/10.1039/B704980C
(48) Spackman, M. A.; McKinnon, J. J. Fingerprinting Intermolecular Interactions in Molecular Crystals. CrystEngComm 2002, 4 (66), 378–392.
https://doi.org/10.1039/B203191B
(49) Spackman, P. R.; Turner, M. J.; McKinnon, J. J.; Wolff, S. K.; Grimwood, D. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer: A Program for Hirshfeld Surface Analysis, Visualization and Quantitative Analysis of Molecular Crystals. urn:issn:1600-5767 2021, 54 (3), 1006–1011. https://doi.org/10.1107/S1600576721002910
(50) Thaçi, V.; Reka, A. A.; Ristovska, N.; Hoti, R.; Berisha, A.; Bogdanov, J. Experimental and Theoretical Studies on (2E,5E)-2,5-Bis(2-Methoxybenzylidene)Cyclopentanone: Structural, Electrochemical, Spectroscopic Features, Solid-State Interactions, Molecular Docking and Adsorption Studies onto 2D Carbon Nanomaterials. Maced. J. Chem. Chem. Eng. 2023, 42 (2), 175-194–175–194. https://doi.org/10.20450/MJCCE.2023.2727
(51) Lee, J. J.; Sobolev, A. N.; Turner, M. J.; Fuller, R. O.; Iversen, B. B.; Koutsantonis, G. A.; Spackman, M. A. Molecular Imprisonment: Host Response to Guest Location, Orientation, and Dynamics in Clathrates of Dianin’s Compound. Cryst. Growth Des. 2014, 14 (3), 1296–1306. https://doi.org/10.1021/CG4018129/SUPPL_FILE/CG4018129_SI_002.CIF
(52) Bakheit, A. H.; Abuelizz, H. A.; Al-Salahi, R. Hirshfeld Surface Analysis and Density Functional Theory Calculations of 2-Benzyloxy-1,2,4-Triazolo[1,5-a] Quinazolin-5(4H)-One: A Comprehensive Study on Crystal Structure, Intermolecular Interactions, and Electronic Properties. Cryst. 2023, Vol. 13, Page 1410 2023, 13 (10), 1410.
https://doi.org/10.3390/CRYST13101410
(53) Turner, M. J.; Thomas, S. P.; Shi, M. W.; Jayatilaka, D.; Spackman, M. A. Energy Frameworks: Insights into Interaction Anisotropy and the Mechanical Properties of Molecular Crystals. Chem. Commun. 2015, 51 (18), 3735–3738. https://doi.org/10.1039/C4CC09074H.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Avni Berisha
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
