{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:53:03Z","timestamp":1792068783305,"version":"4.4.0"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"41","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2021\/42\/E\/ST4\/00229"],"award-info":[{"award-number":["UMO-2021\/42\/E\/ST4\/00229"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The hydrophobic effect is often considered a major driving force for molecular recognition in water, whether through classical desolvation of nonpolar surfaces or through the release of confined high-energy water from host cavities. However, the interplay between protonation, ion\u2013dipole interactions, and hydration remains poorly understood. Here we show that amino-acid recognition by cucurbit[7]uril (CB7) is best described as a population-weighted ensemble of proton-linked hydration states, rather than as a single water-release process. By combining pH-dependent isothermal titration calorimetry, X-ray crystallography, molecular dynamics simulations, and interaction-energy analysis, we connect the pH-dependent apparent binding affinities with cavity and portal hydration coupled to ammonium\u2013portal ion\u2013dipole stabilization. Aromatic amino acids differ not by adopting fundamentally different binding modes, but by redistributing population among four hydration states defined by the position of water relative to the cavity and ammonium anchor. Phe and Trp represent opposite limits, with Phe favoring cooperative cavity-water contact and Trp dominated by dry-cavity filling, whereas Tyr and DOPA shift the ensemble toward portal-solvated states. These results show that confined water can strengthen, rather than oppose, hydrophobic recognition when integrated into the ion\u2013dipole binding motif and proton linkage. CB7\u2013amino-acid recognition therefore emerges as a coupled process in which hydrophobic inclusion, ammonium anchoring, hydration, and proton linkage act together.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c05008","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:02:06Z","timestamp":1788951726000},"page":"10961-10969","source":"Crossref","is-referenced-by-count":0,"title":["Hydration Ensembles\nin Proton-Linked Amino-Acid Recognition\nby Cucurbit[7]uril"],"prefix":"10.1021","volume":"130","author":[{"given":"Ewelina","family":"Zaorska","sequence":"first","affiliation":[{"name":"University of Warsaw , , Pasteura 1 , ,","place":["Warsaw, Poland, 02-093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasza","family":"Jakubik","sequence":"additional","affiliation":[{"name":"University of Warsaw , , Pasteura 1 , ,","place":["Warsaw, Poland, 02-093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0429-9420","authenticated-orcid":true,"given":"David A.","family":"Rinco\u0301n","sequence":"additional","affiliation":[{"name":"University of Warsaw , , Pasteura 1 , ,","place":["Warsaw, Poland, 02-093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakumar","family":"Gurusamy","sequence":"additional","affiliation":[{"name":"University of Warsaw , , Pasteura 1 , ,","place":["Warsaw, Poland, 02-093"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7138-7041","authenticated-orcid":true,"given":"Maura","family":"Malinska","sequence":"additional","affiliation":[{"name":"University of Warsaw , , Pasteura 1 , ,","place":["Warsaw, Poland, 02-093"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2026101508071676200_cit1","doi-asserted-by":"publisher","first-page":"10240","DOI":"10.1039\/C9SC03282G","article-title":"Preferential\nbinding of unsaturated hydrocarbons in aryl-bisimidazolium\u00b7cucurbit[8]uril\ncomplexes furbishes evidence for small-molecule \u03c0\u2013\u03c0 interactions","volume":"10","author":"Barrow","year":"2019","journal-title":"Chem. Sci."},{"key":"2026101508071676200_cit2","doi-asserted-by":"publisher","first-page":"11158","DOI":"10.1002\/anie.201310958","article-title":"The Hydrophobic Effect Revisited\u2500Studies\nwith Supramolecular Complexes Imply High-Energy Water as a Noncovalent\nDriving Force","volume":"53","author":"Biedermann","year":"2014","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026101508071676200_cit3","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1038\/s41557-018-0146-0","article-title":"Cavitation\nenergies can outperform dispersion interactions","volume":"10","author":"He","year":"2018","journal-title":"Nat. Chem."},{"key":"2026101508071676200_cit4","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s10847-004-8835-7","article-title":"Cucurbiturils\u2013a New Family\nof Host Molecules","volume":"50","author":"Kim","year":"2004","journal-title":"J. Inclusion Phenom. Macrocyclic\nChem."},{"key":"2026101508071676200_cit5","doi-asserted-by":"publisher","first-page":"15959","DOI":"10.1021\/ja055013x","article-title":"The Cucurbit[n]uril\nFamily: Prime\nComponents for Self-Sorting Systems","volume":"127","author":"Liu","year":"2005","journal-title":"J. Am.\nChem. Soc."},{"key":"2026101508071676200_cit6","doi-asserted-by":"publisher","first-page":"20737","DOI":"10.1073\/pnas.0706407105","article-title":"A synthetic host-guest system achieves avidin-biotin affinity by\novercoming enthalpy\u2013entropy compensation","volume":"104","author":"Rekharsky","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026101508071676200_cit7","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1002\/anie.201309635","article-title":"Cucurbit[7]uril\u00b7Guest Pair with\nan Attomolar Dissociation Constant","volume":"53","author":"Cao","year":"2014","journal-title":"Angew. Chem.,\nInt. Ed."},{"key":"2026101508071676200_cit8","doi-asserted-by":"publisher","first-page":"5722","DOI":"10.1021\/jacs.6b02682","article-title":"Interaction Entropy: A New Paradigm for Highly Efficient\nand Reliable Computation of Protein\u2013Ligand Binding Free Energy","volume":"138","author":"Duan","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026101508071676200_cit9","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1021\/acs.jpcb.0c11383","article-title":"Evaluating the Performance of Water Models with Host\u2013Guest\nForce Fields in Binding Enthalpy Calculations for Cucurbit[7]uril\u2013Guest\nSystems","volume":"125","author":"C\u0327\u0131narog\u0306lu","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"2026101508071676200_cit10","volume-title":"Binding and Linkage: Functional\nChemistry of Biological Macromolecules","author":"Wyman","year":"1990"},{"key":"2026101508071676200_cit11","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202200529","article-title":"The Role of Packing, Dispersion,\nElectrostatics, and Solvation in High-Affinity Complexes of Cucurbit[n]urils\nwith Uncharged Polar Guests","volume":"28","author":"Grimm","year":"2022","journal-title":"Chem. \u2013\nEur. J."},{"key":"2026101508071676200_cit12","doi-asserted-by":"publisher","first-page":"15400","DOI":"10.1021\/bi9814991","article-title":"Calorimetric Investigation\nof Proton Linkage by Monitoring\nboth the Enthalpy and Association Constant of Binding: Application\nto the Interaction of the Src SH2 Domain with a High-Affinity Tyrosyl\nPhosphopeptide","volume":"37","author":"Bradshaw","year":"1998","journal-title":"Biochemistry"},{"key":"2026101508071676200_cit13","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jct.2012.02.008","article-title":"Strategies\nfor assessing proton linkage\nto bimolecular interactions by global analysis of isothermal titration\ncalorimetry data","volume":"52","author":"Coussens","year":"2012","journal-title":"J. Chem. Thermodyn."},{"key":"2026101508071676200_cit14","doi-asserted-by":"publisher","first-page":"5806","DOI":"10.1021\/ja0319846","article-title":"Mechanism\nof Host\u2013Guest Complexation\nby Cucurbituril","volume":"126","author":"Ma\u0301rquez","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"2026101508071676200_cit15","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1002\/ijch.201100044","article-title":"Deep Inside\nCucurbiturils: Physical\nProperties and Volumes of their Inner Cavity Determine the Hydrophobic\nDriving Force for Host\u2013Guest Complexation","volume":"51","author":"Nau","year":"2011","journal-title":"Isr. J. Chem."},{"key":"2026101508071676200_cit16","doi-asserted-by":"publisher","first-page":"15318","DOI":"10.1021\/ja303309e","article-title":"Release of\nHigh-Energy Water as an Essential Driving Force for the High-Affinity\nBinding of Cucurbit[n]urils","volume":"134","author":"Biedermann","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"2026101508071676200_cit17","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202505713","article-title":"Thermodynamics of\nWater Displacement from Binding Sites and its Contributions to Supramolecular\nand Biomolecular Affinity","volume":"64","author":"Setiadi","year":"2025","journal-title":"Angew. Chem., Int.\nEd."},{"key":"2026101508071676200_cit18","doi-asserted-by":"publisher","first-page":"5216","DOI":"10.1021\/acs.chemrev.5b00583","article-title":"Experimental Binding Energies in\nSupramolecular Complexes","volume":"116","author":"Biedermann","year":"2016","journal-title":"Chem. Rev."},{"key":"2026101508071676200_cit19","doi-asserted-by":"publisher","DOI":"10.1002\/open.202200028","article-title":"When Molecules\nMeet in Water-Recent Contributions of Supramolecular Chemistry to\nthe Understanding of Molecular Recognition Processes in Water","volume":"11","author":"Kubik","year":"2022","journal-title":"ChemistryOpen"},{"key":"2026101508071676200_cit20","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s10847-021-01113-2","article-title":"A molecular\ndynamics study of the complexation of tryptophan, phenylalanine and\ntyrosine amino acids with cucurbit[7]uril","volume":"102","author":"Bodoor","year":"2022","journal-title":"J.\nInclusion Phenom. Macrocyclic Chem."},{"key":"2026101508071676200_cit21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s40010-013-0101-9","article-title":"Cucurbituril-Induced\nSupramolecular pKa Shift in Fluorescent Dyes and Its Prospective Applications","volume":"84","author":"Barooah","year":"2014","journal-title":"Proc. Natl. Acad. Sci., India, Sect. A"},{"key":"2026101508071676200_cit22","doi-asserted-by":"publisher","first-page":"3683","DOI":"10.1021\/jp212459r","article-title":"Stimulus-Responsive\nSupramolecular pKa Tuning of Cucurbit[7]uril Encapsulated Coumarin\n6 Dye","volume":"116","author":"Barooah","year":"2012","journal-title":"J. Phys. Chem. B"},{"key":"2026101508071676200_cit23","doi-asserted-by":"publisher","first-page":"14131","DOI":"10.1039\/C9CC07687E","article-title":"Binding affinities\nof cucurbit[n]urils\nwith cations","volume":"55","author":"Zhang","year":"2019","journal-title":"Chem. Commun."},{"key":"2026101508071676200_cit24","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1016\/S0006-3495(96)79403-1","article-title":"Evaluation of linked\nprotonation effects in protein\nbinding reactions using isothermal titration calorimetry","volume":"71","author":"Baker","year":"1996","journal-title":"Biophys. J."},{"key":"2026101508071676200_cit25","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.1021\/acs.jpcb.5b00743","article-title":"Deciphering\nthe Specific High-Affinity Binding of Cucurbit[7]uril to Amino Acids\nin Water","volume":"119","author":"Lee","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"2026101508071676200_cit26","doi-asserted-by":"publisher","DOI":"10.1002\/qua.26491","article-title":"Binding properties\nof cucurbit[7]uril to neutral and protonated amino acids: A theoretical\nstudy","volume":"121","author":"Ma","year":"2021","journal-title":"Int. J. Quantum Chem."},{"key":"2026101508071676200_cit27","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1002\/ijch.201100035","article-title":"Molecular Recognition of Amino Acids, Peptides, and\nProteins by Cucurbit[n]uril Receptors","volume":"51","author":"Urbach","year":"2011","journal-title":"Isr.\nJ. Chem."},{"key":"2026101508071676200_cit28","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1039\/C2OB27007B","article-title":"Selective molecular recognition of methylated lysines\nand arginines by cucurbit[6]uril and cucurbit[7]uril in aqueous solution","volume":"11","author":"Gamal-Eldin","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"2026101508071676200_cit29","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202302250","article-title":"Cucurbit[7]uril-mediated Histidine Dimerization: Exploring\nthe Structure and Binding Mechanism","volume":"30","author":"Zaorska","year":"2024","journal-title":"Chem. \u2013\nEur. J."},{"key":"2026101508071676200_cit30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1107\/S2053273314026370","article-title":"SHELXT\n\u2013 Integrated space-group and crystal-structure determination","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr., Sect. A: Found. Adv."},{"key":"2026101508071676200_cit31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1107\/S2053229614024218","article-title":"Crystal\nstructure refinement with SHELXL","volume":"71","author":"Sheldrick","year":"2015","journal-title":"Acta Crystallogr.,\nSect. C: Struct. Chem."},{"key":"2026101508071676200_cit32","doi-asserted-by":"publisher","first-page":"7835","DOI":"10.1021\/acs.jcim.5c01063","article-title":"Recent Developments\nin Amber Biomolecular Simulations","volume":"65","author":"Case","year":"2025","journal-title":"J. Chem.\nInf. Model."},{"key":"2026101508071676200_cit33","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/wcms.81","article-title":"The ORCA program\nsystem","volume":"2","author":"Neese","year":"2012","journal-title":"WIREs Comput. Mol. Sci."},{"key":"2026101508071676200_cit34","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.70019","article-title":"Software Update:\nThe ORCA Program System\u2500Version 6.0","volume":"15","author":"Neese","year":"2025","journal-title":"WIREs Comput. Mol. Sci."},{"key":"2026101508071676200_cit35","doi-asserted-by":"publisher","DOI":"10.1063\/5.0040021","article-title":"r2SCAN-3c: A \u2018Swiss\narmy knife\u2019 composite electronic-structure method","volume":"154","author":"Grimme","year":"2021","journal-title":"J. Chem. Phys."},{"key":"2026101508071676200_cit36","doi-asserted-by":"publisher","first-page":"6378","DOI":"10.1021\/jp810292n","article-title":"Universal\nSolvation Model Based on\nSolute Electron Density and on a Continuum Model of the Solvent Defined\nby the Bulk Dielectric Constant and Atomic Surface Tensions","volume":"113","author":"Marenich","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"2026101508071676200_cit37","doi-asserted-by":"publisher","DOI":"10.1063\/1.3521275","article-title":"Nonlocal van der Waals density functional: The simpler\nthe better","volume":"133","author":"Vydrov","year":"2010","journal-title":"J. Chem. Phys."},{"key":"2026101508071676200_cit38","doi-asserted-by":"publisher","first-page":"3866","DOI":"10.1021\/ct200644w","article-title":"Performance of the van der Waals Density Functional\nVV10 and (hybrid)GGA Variants for Thermochemistry and Noncovalent\nInteractions","volume":"7","author":"Hujo","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"2026101508071676200_cit39","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1039\/b515623h","article-title":"Accurate Coulomb-fitting\nbasis sets for H to Rn","volume":"8","author":"Weigend","year":"2006","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2026101508071676200_cit40","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1080\/00268977000101561","article-title":"The calculation of\nsmall molecular interactions by\nthe differences of separate total energies. Some procedures with reduced\nerrors","volume":"19","author":"Boys","year":"1970","journal-title":"Mol. Phys."}],"container-title":["The Journal of Physical\nChemistry B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpcb.6c05008","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/41\/10961\/68456092\/acs.jpcb.6c05008.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/41\/10961\/68456092\/acs.jpcb.6c05008.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:29:13Z","timestamp":1792067353000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article\/130\/41\/10961\/5426814\/Hydration-Ensembles-in-Proton-Linked-Amino-Acid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":40,"journal-issue":{"issue":"41","published-online":{"date-parts":[[2026,9,9]]},"published-print":{"date-parts":[[2026,10,15]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpcb.6c05008","relation":{},"ISSN":["1520-6106","1520-5207"],"issn-type":[{"value":"1520-6106","type":"print"},{"value":"1520-5207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}