{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:20:36Z","timestamp":1788326436118,"version":"build-2803163510"},"reference-count":103,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Caffeine (1,3,7-trimethylxanthine) is a widely consumed psychoactive drug and neurostimulant, yet its molecular organization and permeation behavior in lipid membranes are not fully understood. We employ microseconds-long, united-atom molecular dynamics simulations to investigate caffeine interactions with a solvated DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) bilayer at its fluid phase. Caffeine molecules initially aggregate in the aqueous phase to form ordered stackings, which successively permeate into the membrane. The stacked assemblies gradually dissolve, reaching a stable dispersed state where caffeine molecules preferentially reside near the headgroup\u2013acyl chain interface and orient parallel to the lipid acyl chains, consistent with previous experimental and simulation studies. Simulations initiated with caffeine in the membrane hydrophobic phase converge to the same equilibrium state, indicating a preferred localization at the interface region. Present simulation findings are further supported by free-energy calculations that demonstrate caffeine\u2019s high affinity at the headgroup\u2013acyl chain interface. Caffeine partitioning transiently and slightly reduces bilayer thickness and increases the membrane surface area while enhancing acyl chain stiffness near the hydrophilic part of the membrane. These observed trends are reproducible over different system sizes and independent simulations. Overall, this study provides atomic-level insights into the caffeine permeation process, including its effect on the lipid bilayer structure.<\/jats:p>","DOI":"10.3390\/ijms27177704","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:31:13Z","timestamp":1788251473000},"page":"7704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Insights into Caffeine Stacking, Partitioning, and Organization in DPPC Lipid Bilayers from Microseconds-Long Molecular Dynamics Simulations"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8239-0254","authenticated-orcid":false,"given":"Subhalaxmi","family":"Das","sequence":"first","affiliation":[{"name":"School of Applied Sciences, KIIT Deemed to be University, Bhubaneswar, Khurda 751024, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2762-270X","authenticated-orcid":false,"given":"Nikos Ch.","family":"Karayiannis","sequence":"additional","affiliation":[{"name":"Institute for Optoelectronic Systems and Microtechnology (ISOM) and Escuela T\u00e9cnica Superior de Ingenieros Industriales (ETSII), Universidad Polit\u00e9cnica de Madrid (UPM), Jos\u00e9 Guti\u00e9rrez Abascal 2, E-28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-1968","authenticated-orcid":false,"given":"Supriya","family":"Roy","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, KIIT Deemed to be University, Bhubaneswar, Khurda 751024, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1002\/cphc.202000219","article-title":"Molecular Dynamics Simulation of Small Molecules Interacting with Biological Membranes","volume":"21","author":"Martinotti","year":"2020","journal-title":"ChemPhysChem"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.phrs.2016.06.030","article-title":"In silico pharmacology: Drug membrane partitioning and crossing","volume":"111","author":"Fabre","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1111\/febs.12286","article-title":"Molecular dynamics simulations of the interactions of medicinal plant extracts and drugs with lipid bilayer membranes","volume":"280","author":"Telenius","year":"2013","journal-title":"FEBS J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Smith, A. (2005). Caffeine. Nutritional Neuroscience, CRC Press\/Taylor & Francis.","DOI":"10.1201\/9780203564554.ch20"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Romero-Mart\u00ednez, B.S., Monta\u00f1o, L.M., Sol\u00eds-Chagoy\u00e1n, H., Sommer, B., Ram\u00edrez-Salinas, G.L., P\u00e9rez-Figueroa, G.E., and Flores-Soto, E. (2021). Possible Beneficial Actions of Caffeine in SARS-CoV-2. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115460"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bawornruttanaboonya, K., Chindapan, N., and Devahastin, S. (2025). Numerical Investigation of Conventional and Ultrasound-Assisted Aqueous Extraction of Caffeine from Whole Green Robusta Coffee Beans: Extraction Enhancement via Changing of Extraction Water. Foods, 14.","DOI":"10.3390\/foods14111956"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Di Pietrantonio, D., Pace Palitti, V., Cichelli, A., and Tacconelli, S. (2024). Protective Effect of Caffeine and Chlorogenic Acids of Coffee in Liver Disease. Foods, 13.","DOI":"10.3390\/foods13142280"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1423-0127-17-4","article-title":"Caffeine and a selective adenosine A2A receptor antagonist induce sensitization and cross-sensitization behavior associated with increased striatal dopamine in mice","volume":"17","author":"Hsu","year":"2010","journal-title":"J. Biomed. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Do, H.N., Akhter, S., and Miao, Y. (2021). Pathways and Mechanism of Caffeine Binding to Human Adenosine A2A Receptor. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.673170"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Cruz, L., Salamone, J.D., and Correa, M. (2018). Caffeine and selective adenosine receptor antagonists as new therapeutic tools for the motivational symptoms of depression. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00526"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ruggiero, M., Calvello, R., Porro, C., Messina, G., Cianciulli, A., and Panaro, M.A. (2022). Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112958"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12263-015-0501-3","article-title":"Coffee provides a natural multitarget pharmacopeia against the hallmarks of cancer","volume":"10","author":"Gaascht","year":"2015","journal-title":"Genes Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1080\/07391102.2020.1835732","article-title":"Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2","volume":"40","author":"Elzupir","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Saraiva, S.M., Jacinto, T.A., Gon\u00e7alves, A.C., Gaspar, D., and Silva, L.R. (2023). Overview of Caffeine Effects on Human Health and Emerging Delivery Strategies. Pharmaceuticals, 16.","DOI":"10.20944\/preprints202305.1255.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1053\/j.ajkd.2021.04.018","article-title":"Coffee and Caffeine Consumption and Risk of Kidney Stones: A Mendelian Randomization Study","volume":"79","author":"Yuan","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4552","DOI":"10.1016\/j.csbj.2023.09.023","article-title":"Caffeine causes cell cycle arrest at G0\/G1 and increases of ubiquitinated proteins, ATP and mitochondrial membrane potential in renal cells","volume":"21","author":"Kanlaya","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ejim.2020.04.018","article-title":"Coffee Consumption is Associated with a Decreased Risk of Incident Chronic Kidney Disease: A Systematic Review and Meta-analysis of Cohort Studies","volume":"77","author":"Srithongkul","year":"2020","journal-title":"Eur. J. Intern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"689","DOI":"10.4254\/wjh.v9.i15.689","article-title":"Coffee: The magical bean for liver diseases","volume":"9","author":"Heath","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8249","DOI":"10.3168\/jds.2023-23631","article-title":"Molecular insight into binding behavior of caffeine with lactoferrin: Spectroscopic, molecular docking, and simulation study","volume":"106","author":"Li","year":"2023","journal-title":"J. Dairy Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.15698\/mic2025.06.852","article-title":"Dissecting the cell cycle regulation, DNA damage sensitivity and lifespan effects of caffeine in fission yeast","volume":"12","author":"Alao","year":"2025","journal-title":"Microb. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lin, Z., Wei, J., Hu, Y., Pi, D., Jiang, M., and Lang, T. (2023). Caffeine Synthesis and Its Mechanism and Application by Microbial Degradation, A Review. Foods, 12.","DOI":"10.3390\/foods12142721"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rodak, K., Kokot, I., and Kratz, E.M. (2021). Caffeine as a factor influencing the functioning of the human body\u2014Friend or foe?. Nutrients, 13.","DOI":"10.3390\/nu13093088"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s12024-016-9786-9","article-title":"Caffeine toxicity in forensic practice: Possible effects and under-appreciated sources","volume":"12","author":"Musgrave","year":"2016","journal-title":"Forensic Sci. Med. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"aamag162.5183.","DOI":"10.1093\/ajrccm\/aamag162.5183","article-title":"C53-48 Beyond the Morning Cup: Severe Caffeine Intoxication Presenting as Metabolic and Electrical Instability","volume":"212","author":"Sonti","year":"2026","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_25","first-page":"e66634","article-title":"Death Due to Caffeine and Methamphetamine Toxicity: A Case Report","volume":"16","author":"Kim","year":"2024","journal-title":"Cureus"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1093\/jat\/bkae046","article-title":"Beyond the buzz: The fatal consequences of caffeine overconsumption","volume":"48","author":"Brower","year":"2024","journal-title":"J. Anal. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2174\/1570159X13666141210215655","article-title":"Caffeine: Cognitive and Physical Performance Enhancer or Psychoactive Drug?","volume":"13","author":"Cappelletti","year":"2015","journal-title":"Curr. Neuropharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"139814","DOI":"10.1016\/j.jcis.2025.139814","article-title":"Molecular view of the interactions between the amphiphilic drug propranolol hydrochloride and model lipid membranes","volume":"708","author":"Yan","year":"2026","journal-title":"J. Colloid Interface Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"154701","DOI":"10.1063\/5.0027953","article-title":"Caffeine modulates the dynamics of DODAB membranes: Role of the physical state of the bilayer","volume":"128","author":"Sharma","year":"2020","journal-title":"J. Appl. Phys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1021\/acs.molpharmaceut.1c00009","article-title":"Recent Experimental Developments in Studying Passive Membrane Transport of Drug Molecules","volume":"18","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1016\/j.bbamem.2016.06.025","article-title":"Biophysics in cancer: The relevance of drug-membrane interaction studies","volume":"1858","author":"Alves","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)-Biomembr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20170012","DOI":"10.1515\/revac-2017-0012","article-title":"Analytical techniques and methods for study of drug-lipid membrane interactions","volume":"37","author":"Li","year":"2018","journal-title":"Rev. Anal. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1023\/A:1020182404940","article-title":"NMR Studies of Drug Interaction with Membranes and Membrane-Associated Proteins","volume":"22","author":"Xu","year":"2002","journal-title":"Biosci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1039\/b813853m","article-title":"Drug interactions with lipid membranes","volume":"38","author":"Seddon","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1021\/mp9000662","article-title":"Biophysical Interactions with Model Lipid Membranes: Applications in Drug Discovery and Drug Delivery","volume":"6","author":"Peetla","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1021\/jp311802x","article-title":"Molecular insight into affinities of drugs and their metabolites to lipid bilayers","volume":"117","author":"Berka","year":"2013","journal-title":"J. Phys. Chem. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1021\/jp4112052","article-title":"Amphiphilic drug-like molecules accumulate in a membrane below the head group region","volume":"118","author":"Devane","year":"2014","journal-title":"J. Phys. Chem. B"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7101","DOI":"10.1039\/C6CP08104E","article-title":"Partitioning of caffeine in lipid bilayers reduces membrane fluidity and increases membrane thickness","volume":"19","author":"Khondker","year":"2017","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10174","DOI":"10.1021\/acs.jpcb.1c04360","article-title":"Interaction of Caffeine with Model Lipid Membranes","volume":"125","author":"Tavagnacco","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10957","DOI":"10.1021\/jp2021352","article-title":"Molecular Dynamics Simulation Studies of Caffeine Aggregation in Aqueous Solution","volume":"115","author":"Tavagnacco","year":"2011","journal-title":"J. Phys. Chem. B"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13478","DOI":"10.1039\/C5CP07326J","article-title":"Stacking of purines in water: The role of dipolar interactions in caffeine","volume":"18","author":"Tavagnacco","year":"2016","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9987","DOI":"10.1021\/acs.jpcb.6b06980","article-title":"Stacking and Branching in Self-Aggregation of Caffeine in Aqueous Solution: From the Supramolecular to Atomic Scale Clustering","volume":"120","author":"Tavagnacco","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Das, S., Karayiannis, N.C., and Roy, S. (2025). DPPC Membrane Under Lateral Compression and Stretching to Extreme Limits: Phase Transitions and Rupture. Membranes, 15.","DOI":"10.20944\/preprints202503.2138.v1"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kitjanon, J., Nisoh, N., Phongphanphanee, S., Chattham, N., Karttunen, M., and Wong-ekkabut, J. (2024). Dispersion of Hydrophilic Nanoparticles in Natural Rubber with Phospholipids. Polymers, 16.","DOI":"10.3390\/polym16202901"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Guo, X.Y., Peschel, C., Watermann, T., von Rudorff, G.F., and Sebastiani, D. (2017). Cluster formation of polyphilic molecules solvated in a DPPC bilayer. Polymers, 9.","DOI":"10.3390\/polym9100488"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Przyby\u0142ek, M., Be\u0142dowski, P., Ledzi\u0144ski, D., Lutowski, Z., Mazurkiewicz, A., Raczy\u0144ski, P., Dedinaite, A., and Claesson, P.M. (2024). Molecular Insights into the Interactions Between Human Serum Albumin and Phospholipid Membranes. Appl. Sci., 14.","DOI":"10.20944\/preprints202411.0036.v1"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"20365","DOI":"10.3390\/ijms151120365","article-title":"Interactions of borneol with DPPC phospholipid membranes: A molecular dynamics simulation study","volume":"15","author":"Yin","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Neupane, S., Cordoyiannis, G., Renner, F.U., and Losada-P\u00e9rez, P. (2019). Real-Time monitoring of interactions between solid-supported lipid vesicle layers and shortand medium-chain length alcohols: Ethanol and 1-pentanol. Biomimetics, 4.","DOI":"10.3390\/biomimetics4010008"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Dai, Y., Xie, Z., and Liang, L. (2022). Pore Formation Mechanism of A-Beta Peptide on the Fluid Membrane: A Combined Coarse-Grained and All-Atomic Model. Molecules, 27.","DOI":"10.3390\/molecules27123924"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"064605","DOI":"10.1103\/PhysRevE.107.064605","article-title":"Fine-tuning of colloidal polymer crystals by molecular simulation","volume":"107","author":"Herranz","year":"2023","journal-title":"Phys. Rev. E"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.comptc.2013.11.025","article-title":"Interaction of caffeine dimers with water molecules","volume":"1028","author":"Senthilnithy","year":"2014","journal-title":"Comput. Theor. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Vrane\u0161, M., Borovi\u0107, T.T., Drid, P., Trivi\u0107, T., Toma\u0161, R., and Jankovi\u0107, N. (2022). Influence of Sodium Salicylate on Self-Aggregation and Caffeine Solubility in Water\u2014A New Hypothesis from Experimental and Computational Data. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112304"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"26906","DOI":"10.1038\/s41598-024-77372-z","article-title":"Reproduction of experimental data for stacked caffeine dimers using various computational methods","volume":"14","author":"Gutierrez","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/0167-7322(95)00918-3","article-title":"Determination of order parameters in realistic atom-based models of liquid crystal systems","volume":"68","author":"Wilson","year":"1996","journal-title":"J. Mol. Liq."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"024901","DOI":"10.1063\/5.0034602","article-title":"Rich phase transitions in strongly confined polymer-nanoparticle mixtures: Nematic ordering, crystallization, and liquid-liquid phase separation","volume":"154","author":"Roy","year":"2021","journal-title":"J. Chem. Phys."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"194504","DOI":"10.1063\/1.4830414","article-title":"Effects of dilute aqueous NaCl solution on caffeine aggregation","volume":"139","author":"Sharma","year":"2013","journal-title":"J. Chem. Phys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11809","DOI":"10.1021\/acs.jmedchem.0c00958","article-title":"Assessing the Perturbing Effects of Drugs on Lipid Bilayers Using Gramicidin Channel-Based in Silico and in Vitro Assays","volume":"63","author":"Sun","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e202213247","DOI":"10.1085\/jgp.202213247","article-title":"Screening for bilayer-active and likely cytotoxic molecules reveals bilayer-mediated regulation of cell function","volume":"155","author":"Peyear","year":"2023","journal-title":"J. Gen. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Grage, S.L., Afonin, S., Kara, S., Buth, G., and Ulrich, A.S. (2016). Membrane thinning and thickening induced by membrane-active amphipathic peptides. Front. Cell Dev. Biol., 4.","DOI":"10.3389\/fcell.2016.00065"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1063\/1.476702","article-title":"A Voronoi analysis of lipid area fluctuation in a bilayer","volume":"109","author":"Shinoda","year":"1998","journal-title":"J. Chem. Phys."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1002\/jcc.21787","article-title":"MDAnalysis: A toolkit for the analysis of molecular dynamics simulations","volume":"32","author":"Denning","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gowers, R.J., Linke, M., Barnoud, J., Reddy, T.J.E., Melo, M.N., Seyler, S.L., Domanski, J., Dotson, D.L., Buchoux, S., and Kenney, I.M. (2016, January 11\u201317). MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations. Proceedings of the 15th Python in Science Conference, Austin, TX, USA.","DOI":"10.25080\/Majora-629e541a-00e"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D graphics environment","volume":"9","author":"Hunter","year":"2007","journal-title":"Comput. Sci. Eng."},{"key":"ref_64","unstructured":"(2026, May 21). Welcome to Python.org. Available online: https:\/\/www.python.org\/."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0304-4157(86)90005-5","article-title":"Structure and properties of mixed-chain phospholipid assemblies","volume":"864","author":"Huang","year":"1986","journal-title":"Biochim. Biophys. Acta (BBA)-Rev. Biomembr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.chemphyslip.2009.07.003","article-title":"Chain asymmetry alters thermotropic and barotropic properties of phospholipid bilayer membranes","volume":"161","author":"Goto","year":"2009","journal-title":"Chem. Phys. Lipids"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s00249-007-0192-9","article-title":"Acyl chain order parameter profiles in phospholipid bilayers: Computation from molecular dynamics simulations and comparison with 2H NMR experiments","volume":"36","author":"Vermeer","year":"2007","journal-title":"Eur. Biophys. J."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"R\u00f3g, T., Girych, M., and Bunker, A. (2021). Mechanistic understanding from molecular dynamics in pharmaceutical research 2: Lipid membrane in drug design. Pharmaceuticals, 14.","DOI":"10.3390\/ph14101062"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"17235","DOI":"10.1038\/srep17235","article-title":"Exploring the Effects on Lipid Bilayer Induced by Noble Gases via Molecular Dynamics Simulations","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1021\/acs.jctc.1c00089","article-title":"Functional Group Distributions, Partition Coefficients, and Resistance Factors in Lipid Bilayers Using Site Identification by Ligand Competitive Saturation","volume":"17","author":"Lind","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible, and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1016\/S0006-3495(97)78845-3","article-title":"Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature","volume":"72","author":"Berger","year":"1997","journal-title":"Biophys. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"148401","DOI":"10.1103\/PhysRevLett.132.148401","article-title":"Molecular Simulations Reveal the Free Energy Landscape and Transition State of Membrane Electroporation","volume":"132","author":"Kasparyan","year":"2024","journal-title":"Phys. Rev. Lett."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Filipe, H.A.L., Loura, L.M.S., and Moreno, M.J. (2023). Permeation of a Homologous Series of NBD-Labeled Fatty Amines through Lipid Bilayers: A Molecular Dynamics Study. Membranes, 13.","DOI":"10.3390\/membranes13060551"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Rossos, G., Hadjikakou, S.K., and Kourkoumelis, N. (2021). Molecular dynamics simulation of 2-benzimidazolyl-urea with dppc lipid membrane and comparison with a copper(Ii) complex derivative. Membranes, 11.","DOI":"10.3390\/membranes11100743"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7785","DOI":"10.1021\/acs.jpcb.1c02503","article-title":"A Data-Driven Dimensionality Reduction Approach to Compare and Classify Lipid Force Fields","volume":"125","author":"Capelli","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1021\/ct200491c","article-title":"Membrane protein simulations using AMBER force field and Berger lipid parameters","volume":"8","author":"Caltabiano","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"27681","DOI":"10.1021\/acs.jpcc.8b07861","article-title":"Selective Transport through the Ultrashort Carbon Nanotubes Embedded in Lipid Bilayers","volume":"122","author":"Zeng","year":"2018","journal-title":"J. Phys. Chem. C"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"9567","DOI":"10.1021\/acs.jpcc.9b00675","article-title":"Encapsulation and Release of Drug Molecule Pregabalin Based on Ultrashort Single-Walled Carbon Nanotubes","volume":"123","author":"Chen","year":"2019","journal-title":"J. Phys. Chem. C"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6225","DOI":"10.1021\/acs.jpcc.5b10635","article-title":"Interaction of Graphene and its Oxide with Lipid Membrane: A Molecular Dynamics Simulation Study","volume":"120","author":"Chen","year":"2016","journal-title":"J. Phys. Chem. C"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"115743","DOI":"10.1016\/j.fct.2025.115743","article-title":"The potential mechanism of methamphetamine-induced mitochondrial dysfunction and cell degeneration via direct permeation across mitochondrial membranes: The study on molecular dynamics simulations and in vitro model","volume":"206","author":"Polvat","year":"2025","journal-title":"Food Chem. Toxicol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s00249-011-0700-9","article-title":"Definition and testing of the GROMOS force-field versions 54A7 and 54B7","volume":"40","author":"Schmid","year":"2011","journal-title":"Eur. Biophys. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1021\/acscentsci.5c00755","article-title":"The Martini 3 Lipidome: Expanded and Refined Parameters Improve Lipid Phase Behavior","volume":"11","author":"Pedersen","year":"2025","journal-title":"ACS Cent. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7812","DOI":"10.1021\/jp071097f","article-title":"The MARTINI Force Field: Coarse Grained Model for Biomolecular Simulations","volume":"111","author":"Marrink","year":"2007","journal-title":"J. Phys. Chem. B"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/08927020601054050","article-title":"Multi-property fitting and parameterization of a coarse grained model for aqueous surfactants","volume":"33","author":"Shinoda","year":"2007","journal-title":"Mol. Simul."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"111539","DOI":"10.1016\/j.commatsci.2022.111539","article-title":"Comparison of all atom and united atom models for thermal transport calculations of amorphous polyethylene","volume":"211","author":"Wu","year":"2022","journal-title":"Comput. Mater. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6757","DOI":"10.1021\/acs.jctc.2c00524","article-title":"Comparison of the United- and All-Atom Representations of (Halo)alkanes Based on Two Condensed-Phase Force Fields Optimized against the Same Experimental Data Set","volume":"18","author":"Oliveira","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"031104","DOI":"10.1063\/1.5020808","article-title":"Review of force fields and intermolecular potentials used in atomistic computational materials research","volume":"5","author":"Harrison","year":"2018","journal-title":"Appl. Phys. Rev."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD\u2014Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Molec. Graph."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/S0006-3495(98)74016-0","article-title":"Adhesion forces of lipids in a phospholipid membrane studied by molecular dynamics simulations","volume":"74","author":"Marrink","year":"1998","journal-title":"Biophys. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0304-4157(00)00016-2","article-title":"Structure of lipid bilayers","volume":"1469","author":"Nagle","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., and Hermans, J. (1981). Interaction Models for Water in Relation to Protein Hydration. Intermolecular Forces, Springer.","DOI":"10.1007\/978-94-015-7658-1_21"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A linear constraint solver for molecular simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1063\/1.447334","article-title":"A unified formulation of the constant temperature molecular dynamics methods","volume":"81","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1080\/00268978400101201","article-title":"A molecular dynamics method for simulations in the canonical ensemble","volume":"52","year":"1984","journal-title":"Mol. Phys."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical dynamics: Equilibrium phase-space distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic transitions in single crystals: A new molecular dynamics method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1080\/00268978300102851","article-title":"Constant pressure molecular dynamics for molecular systems","volume":"50","author":"Klein","year":"1983","journal-title":"Mol. Phys."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4026","DOI":"10.1021\/ct200196m","article-title":"An Automated force field Topology Builder (ATB) and repository: Version 1.0","volume":"7","author":"Malde","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-014-9713-7","article-title":"Testing and validation of the Automated Topology Builder (ATB) version 2.0: Prediction of hydration free enthalpies","volume":"28","author":"Koziara","year":"2014","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1021\/acs.jctc.8b00768","article-title":"Automated topology builder version 3.0: Prediction of solvation free enthalpies in water and hexane","volume":"14","author":"Stroet","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1126\/science.1164772","article-title":"The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist","volume":"322","author":"Jaakola","year":"2008","journal-title":"Science"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7704\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:33:10Z","timestamp":1788323590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7704"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":103,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177704"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177704","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}