{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:08:37Z","timestamp":1790856517980,"version":"4.1.0"},"reference-count":81,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1148522N"],"award-info":[{"award-number":["1148522N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Cation\u2013\u03c0 interactions are widely considered key contributors to protein structure and molecular recognition, with quantum chemical studies often predicting substantial stabilization energies. However, their actual prevalence and strength in protein environments remain debated. Here, we combine high\u2010level quantum chemical calculations with large\u2010scale statistical analyses of high\u2010resolution protein structures to reassess the role of lysine\u2013\u03c0 interactions. While gas\u2010phase calculations confirm strong cation\u2013\u03c0 binding for idealized geometries, with corresponding energies of \u221219.0\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    and \u221216.0\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    for Lys\u2010Phe and Arg\u2010Phe pairs respectively, we demonstrate that even small geometric distortions and the inclusion of dielectric screening significantly reduce interaction energies to respective values of \u22125.9\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    and \u22126.5\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    at a dielectric constant of 6 and to \u22123.7\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    and \u22124.7\u2009kcal\u00b7mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    at a dielectric constant of 78. By leveraging the current size of the Protein Data Bank, we analyzed a much larger set of high\u2010resolution protein structures than previously feasible, enabling a more rigorous evaluation of the structural prevalence of lysine\u2013\u03c0 interactions. Our statistical analysis reveals a low occurrence of geometries consistent with optimal cation\u2013\u03c0 interactions. By bridging quantum chemical results with structural data, this work reconciles the discrepancy between strong intrinsic interaction energies and their limited manifestation in proteins. These findings highlight the importance of geometric and environmental effects and suggest that Lys\u2013\u03c0 interactions in proteins are context\u2010dependent and likely contribute less to protein structure than previously assumed.\n                  <\/jats:p>","DOI":"10.1111\/febs.70750","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:41:26Z","timestamp":1790854886000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of cation\u2010\u03c0 interactions using quantum chemistry\u00a0and statistical analysis of high\u2010resolution protein structures"],"prefix":"10.1111","author":[{"given":"Hessel","family":"Poelman","sequence":"first","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Medical Biochemistry  The Netherlands"},{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Eeckhoudt","sequence":"additional","affiliation":[{"name":"Algemene Chemie (ALGC), Department of Chemistry Vrije Universiteit Brussel (VUB)  Elsene Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanin","family":"Wichapong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM) Maastricht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Vriend","sequence":"additional","affiliation":[{"name":"BIPS  Poblacion BACO, Mindoro Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Lutgens","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Medical Biochemistry  The Netherlands"},{"name":"Department of Cardiovascular Medicine and Immunology Mayo Clinic  Rochester MN USA"},{"name":"Department of Immunology Mayo Clinic  Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Alonso","sequence":"additional","affiliation":[{"name":"Algemene Chemie (ALGC), Department of Chemistry Vrije Universiteit Brussel (VUB)  Elsene Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-0412","authenticated-orcid":false,"given":"Gerry A. 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