{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:54:02Z","timestamp":1785783242860,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Robert A. Welch Foundation Grant","award":["W-2057-20210327"],"award-info":[{"award-number":["W-2057-20210327"]}]},{"name":"Robert A. Welch Foundation Grant","award":["OAC 1531594"],"award-info":[{"award-number":["OAC 1531594"]}]},{"name":"Robert A. Welch Foundation Grant","award":["RC1-GM090897"],"award-info":[{"award-number":["RC1-GM090897"]}]},{"name":"National Science Foundation","award":["W-2057-20210327"],"award-info":[{"award-number":["W-2057-20210327"]}]},{"name":"National Science Foundation","award":["OAC 1531594"],"award-info":[{"award-number":["OAC 1531594"]}]},{"name":"National Science Foundation","award":["RC1-GM090897"],"award-info":[{"award-number":["RC1-GM090897"]}]},{"name":"National Institutes of Health","award":["W-2057-20210327"],"award-info":[{"award-number":["W-2057-20210327"]}]},{"name":"National Institutes of Health","award":["OAC 1531594"],"award-info":[{"award-number":["OAC 1531594"]}]},{"name":"National Institutes of Health","award":["RC1-GM090897"],"award-info":[{"award-number":["RC1-GM090897"]}]},{"name":"Williams Endowment of Interdisciplinary Physics at Trinity University","award":["W-2057-20210327"],"award-info":[{"award-number":["W-2057-20210327"]}]},{"name":"Williams Endowment of Interdisciplinary Physics at Trinity University","award":["OAC 1531594"],"award-info":[{"award-number":["OAC 1531594"]}]},{"name":"Williams Endowment of Interdisciplinary Physics at Trinity University","award":["RC1-GM090897"],"award-info":[{"award-number":["RC1-GM090897"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The molecular events of protein misfolding and self-aggregation of tau and amylin are associated with the progression of Alzheimer\u2019s and diabetes, respectively. Recent studies suggest that tau and amylin can form hetero-tau-amylin oligomers. Those hetero-oligomers are more neurotoxic than homo-tau oligomers. So far, the detailed interactions between the hetero-oligomers and the neuronal membrane are unknown. Using multiscale MD simulations, the lipid binding and protein folding behaviors of hetero-oligomers on asymmetric lipid nanodomains or raft membranes were examined. Our raft membranes contain phase-separated phosphatidylcholine (PC), cholesterol, and anionic phosphatidylserine (PS) or ganglioside (GM1) in one leaflet of the lipid bilayer. The hetero-oligomers bound more strongly to the PS and GM1 than other lipids via the hydrophobic and hydrophilic interactions, respectively, in the raft membranes. The hetero-tetramer disrupted the acyl chain orders of both PC and PS in the PS-containing raft membrane, but only the GM1 in the GM1-containing raft membrane as effectively as the homo-tau-tetramer. We discovered that the alpha-helical content in the heterodimer was greater than the sum of alpha-helical contents from isolated tau and amylin monomers on both raft membranes, indicative of a synergetic effect of tau-amylin interactions in surface-induced protein folding. Our results provide new molecular insights into understanding the cross-talk between Alzheimer\u2019s and diabetes.<\/jats:p>","DOI":"10.3390\/molecules29030740","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T07:50:12Z","timestamp":1707205812000},"page":"740","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multiscale Modeling of Macromolecular Interactions between Tau-Amylin Oligomers and Asymmetric Lipid Nanodomains That Link Alzheimer\u2019s and Diabetic Diseases"],"prefix":"10.3390","volume":"29","author":[{"given":"Natalia","family":"Santos","sequence":"first","affiliation":[{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luthary","family":"Segura","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Lewis","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Pham","sequence":"additional","affiliation":[{"name":"Physics Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8128-6079","authenticated-orcid":false,"given":"Kwan H.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"},{"name":"Physics Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1021\/cn500143n","article-title":"Advances in therapeutics for neurodegenerative tauopathies: Moving toward the specific targeting of the most toxic tau species","volume":"5","author":"Gerson","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ijbiomac.2022.11.031","article-title":"Protein misfolding and related human diseases: A comprehensive review of toxicity, proteins involved, and current therapeutic strategies","volume":"223","author":"Khan","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1021\/acs.chemrev.0c00981","article-title":"Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes","volume":"121","author":"Milardi","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.4103\/1673-5374.369095","article-title":"A pancreatic player in dementia: Pathological role for islet amyloid polypeptide accumulation in the brain","volume":"18","author":"Bortoletto","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13024-022-00518-y","article-title":"Islet amyloid polypeptide cross-seeds tau and drives the neurofibrillary pathology in Alzheimer\u2019s disease","volume":"17","author":"Zhang","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e199826","DOI":"10.1001\/jamanetworkopen.2019.9826","article-title":"Association of Plasma Amylin Concentration With Alzheimer Disease and Brain Structure in Older Adults","volume":"2","author":"Zhu","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/path.5674","article-title":"Combination of human tau and islet amyloid polypeptide exacerbates metabolic dysfunction in transgenic mice","volume":"254","author":"Wijesekara","year":"2021","journal-title":"J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.1021\/acschemneuro.9b00516","article-title":"Catalytic Prion-Like Cross-Talk between a Key Alzheimer\u2019s Disease Tau-Fragment R3 and the Type 2 Diabetes Peptide IAPP","volume":"10","author":"Arya","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11259","DOI":"10.1021\/acs.chemrev.8b00322","article-title":"Membrane Lipid Nanodomains","volume":"118","author":"Cebecauer","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7819","DOI":"10.1021\/acs.jpcb.0c03368","article-title":"Capturing Biologically Complex Tissue-Specific Membranes at Different Levels of Compositional Complexity","volume":"124","author":"Ingolfsson","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chiricozzi, E., Lunghi, G., Di Biase, E., Fazzari, M., Sonnino, S., and Mauri, L. (2020). GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030868"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plipres.2014.06.002","article-title":"Phosphatidylserine in the brain: Metabolism and function","volume":"56","author":"Kim","year":"2014","journal-title":"Prog. Lipid Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cheng, K.H., Graf, A., Lewis, A., Pham, T., and Acharya, A. (2022). Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations. Membranes, 12.","DOI":"10.3390\/membranes12111098"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lewis, A., Pham, T., Nguyen, N., Graf, A., and Cheng, K.H. (2023). Lipid domain boundary triggers membrane damage and protein folding of human islet amyloid polypeptide in the early pathogenesis of amyloid diseases. Biophys. Chem., 296.","DOI":"10.1016\/j.bpc.2023.106993"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nguyen, N., Lewis, A., Pham, T., Sikazwe, D., and Cheng, K.H. (2023). Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations. Molecules, 28.","DOI":"10.3390\/molecules28104191"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1021\/acs.chemrev.0c01122","article-title":"Amyloid Oligomers: A Joint Experimental\/Computational Perspective on Alzheimer\u2019s Disease, Parkinson\u2019s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis","volume":"121","author":"Nguyen","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"805","DOI":"10.3390\/macromol3040046","article-title":"Molecular Mechanisms of Protein-Lipid Interactions and Protein Folding of Heterogeneous Amylin and Tau Oligomers on Lipid Nanodomains That Link to Alzheimer\u2019s","volume":"3","author":"Santos","year":"2023","journal-title":"Macromol"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1021\/ct400617g","article-title":"Going Backward: A Flexible Geometric Approach to Reverse Transformation from Coarse Grained to Atomistic Models","volume":"10","author":"Wassenaar","year":"2014","journal-title":"J. Chem. Theory Comput."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.2174\/1871527313666140917095514","article-title":"Protein misfolding and aggregation in Alzheimer\u2019s disease and type 2 diabetes mellitus","volume":"13","author":"Ashraf","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1021\/ct700324x","article-title":"The MARTINI Coarse-Grained Force Field: Extension to Proteins","volume":"4","author":"Monticelli","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12680","DOI":"10.1021\/bi801427c","article-title":"A single mutation in the nonamyloidogenic region of islet amyloid polypeptide greatly reduces toxicity","volume":"47","author":"Brender","year":"2008","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fimmu.2012.00195","article-title":"Does cholesterol play a role in the bacterial selectivity of antimicrobial peptides?","volume":"3","author":"Brender","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s12551-019-00542-1","article-title":"The role of membrane tension in the action of antimicrobial peptides and cell-penetrating peptides in biomembranes","volume":"11","author":"Hasan","year":"2019","journal-title":"Biophys. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.3389\/fimmu.2020.01629","article-title":"Functional Reciprocity of Amyloids and Antimicrobial Peptides: Rethinking the Role of Supramolecular Assembly in Host Defense, Immune Activation, and Inflammation","volume":"11","author":"Lee","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4087","DOI":"10.1038\/s41598-020-61110-2","article-title":"Elastic deformations mediate interaction of the raft boundary with membrane inclusions leading to their effective lateral sorting","volume":"10","author":"Pinigin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11401","DOI":"10.1038\/ncomms11401","article-title":"Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion","volume":"7","author":"Yang","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"011919","DOI":"10.1103\/PhysRevE.75.011919","article-title":"Lateral tension increases the line tension between two domains in a lipid bilayer membrane","volume":"75","author":"Akimov","year":"2007","journal-title":"Phys. Rev. E Stat. Nonlin Soft Matter Phys."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1039\/C6SM02727J","article-title":"High-resolution structure of coexisting nanoscopic and microscopic lipid domains","volume":"13","author":"Belicka","year":"2017","journal-title":"Soft Matter"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17367","DOI":"10.1073\/pnas.0807527105","article-title":"The molecular face of lipid rafts in model membranes","volume":"105","author":"Risselada","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12299","DOI":"10.1073\/pnas.1508483112","article-title":"Dynamic label-free imaging of lipid nanodomains","volume":"112","author":"Danial","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nrm.2017.16","article-title":"The mystery of membrane organization: Composition, regulation and roles of lipid rafts","volume":"18","author":"Sezgin","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Simons, K., and Sampaio, J.L. (2011). Membrane organization and lipid rafts. Cold Spring Harb. Perspect. Biol., 3.","DOI":"10.1101\/cshperspect.a004697"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1021\/acs.jpcb.0c11132","article-title":"Mechanistic Insights into the Co-Aggregation of A\u03b2 and hIAPP: An All-Atom Molecular Dynamic Study","volume":"125","author":"Li","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1021\/acschemneuro.6b00247","article-title":"Molecular Understanding of Abeta-hIAPP Cross-Seeding Assemblies on Lipid Membranes","volume":"8","author":"Zhang","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1021\/ar200189b","article-title":"Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective","volume":"45","author":"Brender","year":"2012","journal-title":"Acc. Chem. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4645","DOI":"10.1021\/acs.jcim.1c00767","article-title":"Distinct Modes of Action of IAPP Oligomers on Membranes","volume":"61","author":"Sepehri","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ct700301q","article-title":"GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"256","DOI":"10.2144\/98252bc02","article-title":"User-friendly and versatile software for analysis of protein hydrophobicity","volume":"25","author":"Han","year":"1998","journal-title":"BioTechniques"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0022-2836(82)90515-0","article-title":"A simple method for displaying the hydropathic character of a protein","volume":"157","author":"Kyte","year":"1982","journal-title":"J. Mol. Biol."},{"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":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Blumer, M., Harris, S., Li, M., Martinez, L., Untereiner, M., Saeta, P.N., Carpenter, T.S., Ingolfsson, H.I., and Bennett, W.F.D. (2020). Simulations of Asymmetric Membranes Illustrate Cooperative Leaflet Coupling and Lipid Adaptability. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00575"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8784","DOI":"10.1021\/acs.jpcb.0c06386","article-title":"Optimization of Slipids Force Field Parameters Describing Headgroups of Phospholipids","volume":"124","author":"Grote","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pham, T., and Cheng, K.H. (2022). Exploring the binding kinetics and behaviors of self-aggregated beta-amyloid oligomers to phase-separated lipid rafts with or without ganglioside-clusters. Biophys. Chem., 290.","DOI":"10.1016\/j.bpc.2022.106874"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cheng, S.Y., Cao, Y., Rouzbehani, M., and Cheng, K.H. (2020). Coarse-grained MD simulations reveal beta-amyloid fibrils of various sizes bind to interfacial liquid-ordered and liquid-disordered regions in phase separated lipid rafts with diverse membrane-bound conformational states. Biophys. Chem., 260.","DOI":"10.1016\/j.bpc.2020.106355"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/j.bpj.2018.01.033","article-title":"CONAN: A Tool to Decode Dynamical Information from Molecular Interaction Maps","volume":"114","author":"Mercadante","year":"2018","journal-title":"Biophys. J."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/3\/740\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:55:16Z","timestamp":1760104516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/3\/740"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,5]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["molecules29030740"],"URL":"https:\/\/doi.org\/10.3390\/molecules29030740","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,5]]}}}