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Thus, we found beneficial effects of K+ on bufadienolide binding, which strongly contrasted with the well-known antagonism between K+ and cardenolides. In order to understand this peculiarity of bufalin interactions, we used docking and molecular dynamics simulations of the complexes involving Na+,K+-ATPase, bufadienolides (bufalin, cinobufagin), and ions (K+, Na+, Mg2+). The results revealed that bufadienolide binding is affected by (i) electrostatic attraction of the lactone ring by a cation and (ii) the ability of a cation to stabilize and \u201cshape\u201d the site constituted by transmembrane helices of the \u03b1-subunit (\u03b1M1\u20136). The latter effect was due to varying coordination patterns involving amino acid residues from helix bundles \u03b1M1\u20134 and \u03b1M5\u201310. Substituents on the steroid core of a bufadienolide add to and modify the cation effects. The above rationale is fully consistent with the ion effects on the kinetics of Na+,K+-ATPase\/bufadienolide interactions.<\/jats:p>","DOI":"10.1021\/acs.jcim.0c01396","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T15:51:58Z","timestamp":1611762718000},"page":"976-986","source":"Crossref","is-referenced-by-count":6,"title":["Beneficent and Maleficent Effects of Cations on Bufadienolide\nBinding to Na+,K+-ATPase"],"prefix":"10.1021","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3832-7781","authenticated-orcid":true,"given":"Lucy Kate","family":"Ladefoged","sequence":"first","affiliation":[{"name":"Aarhus University , , H\u00f8egh-Guldbergsgade 10 , ,","place":["Aarhus C, Denmark, 8000"]},{"name":"Aarhus University , , Langelandsgade 140 , ,","place":["Aarhus C, Denmark, 8000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9937-1562","authenticated-orcid":true,"given":"Birgit","family":"Schi\u00f8tt","sequence":"additional","affiliation":[{"name":"Aarhus University , , Langelandsgade 140 , ,","place":["Aarhus C, Denmark, 8000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-6108","authenticated-orcid":true,"given":"Natalya U.","family":"Fedosova","sequence":"additional","affiliation":[{"name":"Aarhus University , , H\u00f8egh-Guldbergsgade 10 , ,","place":["Aarhus C, Denmark, 8000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"issue":"25","key":"2026092806083854100_cit1","doi-asserted-by":"publisher","first-page":"19582","DOI":"10.1074\/jbc.M110.119248","article-title":"Selectivity of\nDigitalis Glycosides for Isoforms of Human Na,K-ATPase","volume":"285","author":"Katz","year":"2010","journal-title":"J. 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