{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T17:21:23Z","timestamp":1780766483139,"version":"3.54.1"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ICAR_2023"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Nymphaeol A (NYA) is a tetrahydroxyflavanone anchored to a hydrophobic geranyl group, isolated from different sources and a component of propolis, a complex mixture produced by honeybees and used since ancient times as a healthy drug. This complex exhibits significant antioxidant, antifungal, antibacterial, antiviral, anticancer and antimicrobial properties and NYA is one of its main components. NYA is a lipophilic molecule with two domains, one polar and one hydrophobic. NYA can be inserted into membranes, and its membrane properties depend not only on its location but also on the membrane\u2019s lipid composition. This work uses molecular dynamics to obtain the dynamics, orientation, location and interactions of NYA in a complex biomembrane. This work shows that in an aqueous solution, NYA forms high-order aggregates where the molecules are joined together by the hydrophobic chain. In the presence of a membrane but initially located in the aqueous media, NYA is capable of inserting itself spontaneously into the membrane. Inside the membrane, NYA can be found in the monomeric form, as well as forming aggregates, tending to remain in its most extended conformation. NYA moves along the x-, y- and z-axes, with the movement along the z-axis larger than that of the membrane\u2019s lipids. NYA forms an approximate angle of 35\u00b0 perpendicular with respect to the membrane and is inserted between the phospholipid hydrocarbon chains, slightly increasing membrane fluidity. Furthermore, NYA prefers POPC and PSM but not POPE or CHOL. NYA\u2019s location and movement within the membrane should be well-suited for its potent bioactivity.<\/jats:p>","DOI":"10.3390\/membranes15060163","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T06:30:26Z","timestamp":1748413826000},"page":"163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Location and Dynamics of Nymphaeol A in a Complex Membrane"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5148-141X","authenticated-orcid":false,"given":"Jos\u00e9","family":"Villala\u00edn","sequence":"first","affiliation":[{"name":"Institute of Research, Development, and Innovation in Healthcare Biotechnology (IDiBE), Universidad \u201cMiguel Hern\u00e1ndez\u201d, E-03202 Elche-Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105375","DOI":"10.1016\/j.fitote.2022.105375","article-title":"Antioxidant, anti-inflammatory and anti-acne activities of stingless bee (Tetragonula biroi) propolis","volume":"164","author":"Arung","year":"2023","journal-title":"Fitoterapia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1111\/iej.13503","article-title":"Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways","volume":"54","author":"Nam","year":"2021","journal-title":"Int. Endod. J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shahinozzaman, M., Taira, N., Ishii, T., Halim, M.A., Hossain, M.A., and Tawata, S. (2018). Anti-Inflammatory, Anti-Diabetic, and Anti-Alzheimer\u2019s Effects of Prenylated Flavonoids from Okinawa Propolis: An Investigation by Experimental and Computational Studies. Molecules, 23.","DOI":"10.3390\/molecules23102479"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s00114-015-1318-z","article-title":"Chemical composition and antimicrobial activity of honeybee (Apis mellifera ligustica) propolis from subtropical eastern Australia","volume":"102","author":"Massaro","year":"2015","journal-title":"Naturwissenschaften"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"826245","DOI":"10.1155\/2013\/826245","article-title":"Nymphaeol-A Isolated from Okinawan Propolis Suppresses Angiogenesis and Induces Caspase-Dependent Apoptosis via Inactivation of Survival Signals","volume":"2013","author":"Tsuchiya","year":"2013","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.fitote.2012.04.020","article-title":"Flavonoids with antiplasmodial and cytotoxic activities of Macaranga triloba","volume":"83","author":"Zakaria","year":"2012","journal-title":"Fitoterapia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1080\/14786419.2010.535146","article-title":"Chemical modification and anticancer effect of prenylated flavanones from Taiwanese propolis","volume":"26","author":"Chen","year":"2012","journal-title":"Nat. Prod. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ebner, D.W., Woods, D.C., and Tran, T.D. (2025). Bioactive Polyphenolic Compounds from Propolis of Tetragonula carbonaria in the Gibberagee Region, New South Wales, Australia. Foods, 14.","DOI":"10.3390\/foods14060965"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.jobcr.2025.03.013","article-title":"Propolis nanoemulsion extract from celebes stingless bee (Tetragonula biroi) phytochemistry and antibacterial analysis to periodontopathogen bacteria","volume":"15","author":"Amalia","year":"2025","journal-title":"J. Oral Biol. Craniofacial Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"106526","DOI":"10.1016\/j.fitote.2025.106526","article-title":"Propolis: A comprehensive review on the nature\u2019s polyphenolic wonder","volume":"183","author":"Balasubramaniam","year":"2025","journal-title":"Fitoterapia"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Deniz, F.S.S., Orhan, I.E., Filipek, P.A., Ertas, A., Gstir, R., Jakschitz, T., and Bonn, G.K. (2025). Evaluation of the Anti-Aging Properties of Ethanolic Extracts from Selected Plant Species and Propolis by Enzyme Inhibition Assays and 2D\/3D Cell Culture Methods. Pharmaceuticals, 18.","DOI":"10.3390\/ph18030439"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Martinotti, S., Bonsignore, G., and Ranzato, E. (2025). Propolis: A Natural Substance with Multifaceted Properties and Activities. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041519"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"110","DOI":"10.5582\/ddt.2017.01011","article-title":"Frondoside A from sea cucumber and nymphaeols from Okinawa propolis: Natural anti-cancer agents that selectively inhibit PAK1 in vitro","volume":"11","author":"Nguyen","year":"2017","journal-title":"Drug Discov. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S1995-7645(13)60184-4","article-title":"Analysis of antioxidant prenylflavonoids in different parts of Macaranga tanarius, the plant origin of Okinawan propolis","volume":"7","author":"Kumazawa","year":"2014","journal-title":"Asian Pac. J. Trop. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00114-008-0383-y","article-title":"Plant origin of Okinawan propolis: Honeybee behavior observation and phytochemical analysis","volume":"95","author":"Kumazawa","year":"2008","journal-title":"Naturwissenschaften"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7722","DOI":"10.1021\/jf071187h","article-title":"Antioxidant prenylated flavonoids from propolis collected in Okinawa, Japan","volume":"55","author":"Kumazawa","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1271\/bbb.68.260","article-title":"A new prenylated flavonoid from propolis collected in Okinawa, Japan","volume":"68","author":"Kumazawa","year":"2004","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_18","unstructured":"Sood, B., Patel, P., and Keenaghan, M. (2024). Coenzyme Q10. StatPearls, Treasure Island (FL) Ineligible Companies."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cores, A., Carmona-Zafra, N., Clerigue, J., Villacampa, M., and Menendez, J.C. (2023). Quinones as Neuroprotective Agents. Antioxidants, 12.","DOI":"10.3390\/antiox12071464"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3907","DOI":"10.1080\/10408398.2022.2137724","article-title":"Coenzyme Q10 in aging and disease","volume":"64","author":"Gasmi","year":"2024","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1007\/s00204-023-03562-9","article-title":"Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging","volume":"97","author":"Jomova","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/978-1-4419-7347-4_5","article-title":"Endogenous antioxidants and radical scavengers","volume":"698","author":"Rizzo","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.2174\/092986711796957257","article-title":"Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues","volume":"18","author":"Orsucci","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1016\/j.mito.2007.02.006","article-title":"The antioxidant role of coenzyme Q","volume":"7","author":"Bentinger","year":"2007","journal-title":"Mitochondrion"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","article-title":"Hallmarks of neurodegenerative diseases","volume":"186","author":"Wilson","year":"2023","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14554","DOI":"10.1021\/ja507832e","article-title":"Lipid organization of the plasma membrane","volume":"136","author":"Ingolfsson","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1039\/C8MD00166A","article-title":"An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge","volume":"9","author":"Perricone","year":"2018","journal-title":"Medchemcomm"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.freeradbiomed.2024.06.017","article-title":"Location and interaction of idebenone and mitoquinone in a membrane similar to the inner mitochondrial membrane. Comparison with ubiquinone 10","volume":"222","author":"Villalain","year":"2024","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.3390\/jox14030068","article-title":"Bisphenol F and Bisphenol S in a Complex Biomembrane: Comparison with Bisphenol A","volume":"14","author":"Villalain","year":"2024","journal-title":"J. Xenobiot."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"044130","DOI":"10.1063\/5.0014475","article-title":"Scalable molecular dynamics on CPU and GPU architectures with NAMD","volume":"153","author":"Phillips","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03d5, \u03c8 and side-chain \u03c71 and \u03c72 dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types","volume":"114","author":"Klauda","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00249-012-0880-y","article-title":"Molecular dynamics of water in the neighborhood of aquaporins","volume":"42","author":"Ozu","year":"2013","journal-title":"Eur. Biophys. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1002\/jcc.23702","article-title":"CHARMM-GUI Membrane Builder toward realistic biological membrane simulations","volume":"35","author":"Wu","year":"2014","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0006-3495(01)75689-5","article-title":"Effects of phospholipid unsaturation on the membrane\/water interface: A molecular simulation study","volume":"81","author":"Murzyn","year":"2001","journal-title":"Biophys. J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Villalain, J. (2024). Localization and Aggregation of Honokiol in the Lipid Membrane. Antioxidants, 13.","DOI":"10.3390\/antiox13081025"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nrm2330","article-title":"Membrane lipids: Where they are and how they behave","volume":"9","author":"Voelker","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1099\/vir.0.000113","article-title":"Physico-chemical requirements and kinetics of membrane fusion of flavivirus-like particles","volume":"96","author":"Esposito","year":"2015","journal-title":"J. Gen. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1093\/bioinformatics\/btu037","article-title":"MEMBPLUGIN: Studying membrane complexity in VMD","volume":"30","author":"Giorgino","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Galiano, V., and Villalain, J. (2020). Aggregation of 25-hydroxycholesterol in a complex biomembrane. Differences with cholesterol. Biochim. Biophys. Acta Biomembr., 1862.","DOI":"10.1016\/j.bbamem.2020.183413"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Villalain, J. (2022). Envelope E protein of dengue virus and phospholipid binding to the late endosomal membrane. Biochim. Biophys. Acta Biomembr., 1864.","DOI":"10.1016\/j.bbamem.2022.183889"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1080\/07391102.2018.1508372","article-title":"Epigallocatechin-3-gallate location and interaction with late endosomal and plasma membrane model membranes by molecular dynamics","volume":"37","author":"Villalain","year":"2019","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12026","DOI":"10.1080\/07391102.2022.2164521","article-title":"Bergamottin: Location, aggregation and interaction with the plasma membrane","volume":"41","author":"Villalain","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Villalain, J. (2022). Procyanidin C1 Location; Interaction, and Aggregation in Two Complex Biomembranes. Membranes, 12.","DOI":"10.3390\/membranes12070692"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cpc.2013.08.022","article-title":"Computing 1-D atomic densities in macromolecular simulations: The Density Profile Tool for VMD","volume":"185","author":"Giorgino","year":"2014","journal-title":"Comput. Phys. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7882","DOI":"10.1021\/acs.jpcb.5b02135","article-title":"Capturing Spontaneous Membrane Insertion of the Influenza Virus Hemagglutinin Fusion Peptide","volume":"119","author":"Baylon","year":"2015","journal-title":"J. Phys. Chem. B"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.21105\/joss.01698","article-title":"Computing diffusion coefficients in macromolecular simulations: The Diffusion Coefficient Tool for VMD","volume":"4","author":"Giorgino","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ymeth.2006.08.006","article-title":"Setting up and running molecular dynamics simulations of membrane proteins","volume":"41","author":"Kandt","year":"2007","journal-title":"Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9424","DOI":"10.1021\/jp0348981","article-title":"Methodological issues in lipid bilayers simulations","volume":"107","author":"Anezo","year":"2003","journal-title":"J. Phys. Chem. B"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.1021\/acs.jpcb.7b00359","article-title":"Molecular Simulations of Mixed Lipid Bilayers with Sphingomyelin, Glycerophospholipids, and Cholesterol","volume":"121","author":"Bera","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1016\/S0006-3495(04)74227-7","article-title":"Molecular dynamics simulation of a palmitoyl-oleoyl phosphatidylserine bilayer with Na+ counterions and NaCl","volume":"86","author":"Mukhopadhyay","year":"2004","journal-title":"Biophys. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/j.bbamem.2015.02.016","article-title":"Geometrical effects of phospholipid olefinic bonds on the structure and dynamics of membranes: A molecular dynamics study","volume":"1848","author":"Tsai","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/S0006-3495(03)74594-9","article-title":"Effect of sodium chloride on a lipid bilayer","volume":"85","author":"Bockmann","year":"2003","journal-title":"Biophys. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0304-4157(97)00008-7","article-title":"A computer perspective of membranes: Molecular dynamics studies of lipid bilayer systems","volume":"1331","author":"Tieleman","year":"1997","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Membranes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0375\/15\/6\/163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:42:07Z","timestamp":1760031727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0375\/15\/6\/163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,28]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["membranes15060163"],"URL":"https:\/\/doi.org\/10.3390\/membranes15060163","relation":{},"ISSN":["2077-0375"],"issn-type":[{"value":"2077-0375","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,28]]}}}