{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:43:20Z","timestamp":1792611800999,"version":"4.5.0"},"reference-count":114,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010747","name":"Consejo Nacional de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["N024-2019-Fondecyt-BM-INC.INV and CONCYTEC- FONDECYT- E038-01"],"award-info":[{"award-number":["N024-2019-Fondecyt-BM-INC.INV and CONCYTEC- FONDECYT- E038-01"]}],"id":[{"id":"10.13039\/501100010747","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer\u2019s disease. Several studies have shown that ApoE4-Amyloid \u03b2 (A\u03b2) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical A\u03b2 levels, as well as decreases the number of activated astrocytes around A\u03b2 plaques. However, the interactions between enoxaparin and the ApoE4-A\u03b2 proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-A\u03b2 interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-A\u03b2 interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-A\u03b2 complex formation.<\/jats:p>","DOI":"10.3390\/biom12040499","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T15:31:21Z","timestamp":1648222281000},"page":"499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4\u2013Amyloid-Beta (A\u03b2) Complex at Different pH Conditions"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2921-5681","authenticated-orcid":false,"given":"Jorge Alberto","family":"Aguilar-Pineda","sequence":"first","affiliation":[{"name":"Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"},{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2014CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9871-6143","authenticated-orcid":false,"given":"Silvana G.","family":"Paco-Coralla","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9305-7003","authenticated-orcid":false,"given":"Camilo","family":"Febres-Molina","sequence":"additional","affiliation":[{"name":"Doctorado en Fisicoqu\u00edmica Molecular, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago 8370134, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7277-7925","authenticated-orcid":false,"given":"Pamela L.","family":"Gamero-Begazo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2014CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Shrivastava","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7908-8230","authenticated-orcid":false,"given":"Karin J.","family":"Vera-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-9286","authenticated-orcid":false,"given":"Gonzalo","family":"Davila-Del-Carpio","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"},{"name":"Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5853-2833","authenticated-orcid":false,"given":"Patricia","family":"L\u00f3pez-C","sequence":"additional","affiliation":[{"name":"Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-1207","authenticated-orcid":false,"given":"Badhin","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n en Ingenier\u00eda Molecular\u2014CIIM, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Urb. San Jos\u00e9 s\/n\u2014Umacollo, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5491-4375","authenticated-orcid":false,"given":"Christian L.","family":"Lino Cardenas","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer disease: An update on pathobiology and treatment strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2021). 2021 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 17, 327\u2013406.","DOI":"10.1002\/alz.12328"},{"key":"ref_3","first-page":"401","article-title":"Advances in diagnostic testing for Alzheimer disease","volume":"110","author":"Schindler","year":"2013","journal-title":"Mo. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High performance plasma amyloid-\u03b2 biomarkers for Alzheimer\u2019s disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S289","DOI":"10.3233\/JAD-179904","article-title":"A Blood Test for Alzheimer\u2019s Disease: Progress, Challenges, and Recommendations","volume":"64","author":"Kiddle","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/bs.pmbts.2019.08.001","article-title":"Future horizons in Alzheimer\u2019s disease research","volume":"168","author":"Wisniewski","year":"2019","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1212\/CON.0000000000000700","article-title":"Late-onset Alzheimer disease","volume":"25","author":"Rabinovici","year":"2019","journal-title":"Continuum Lifelong Learn. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0304-3940(92)90444-C","article-title":"Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic am-yloid","volume":"135","author":"Wisniewski","year":"1992","journal-title":"Neurosci. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1006\/bbrc.1993.1423","article-title":"Apolipoprotein E: Binding to soluble Alzheimer\u2019s beta-amyloid","volume":"192","author":"Wisniewski","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S0140-6736(95)90701-7","article-title":"Is Alzheimer\u2019s disease an apolipoprotein E amyloidosis?","volume":"345","author":"Wisniewski","year":"1995","journal-title":"The Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/489428","article-title":"Apolipoprotein E: Essential catalyst of the Alzheimer amyloid cascade","volume":"2012","author":"Potter","year":"2012","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3233\/JAD-180740","article-title":"The role of apolipoprotein E isoforms in Alzheimer\u2019s disease","volume":"68","author":"Roda","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1097\/00001756-199507310-00012","article-title":"ApoE genotypes in Australia: Roles in early and late onset Alzheimer\u2019s disease and Down\u2019s syndrome","volume":"6","author":"Martins","year":"1995","journal-title":"Neuroreport"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3233\/JAD-171145","article-title":"Alzheimer\u2019s disease: A journey from amyloid peptides and oxidative stress, to biomarker tech-nologies and disease prevention strategies-gains from AIBL and DIAN cohort studies","volume":"62","author":"Martins","year":"2018","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/ana.21843","article-title":"APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging","volume":"67","author":"Morris","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.neuron.2020.10.008","article-title":"Apolipoprotein E: Structural insights and links to Alzheimer disease pathogenesis","volume":"109","author":"Chen","year":"2021","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.neuron.2014.01.045","article-title":"ApoE and A\u03b2 in Alzheimer\u2019s disease: Accidental encounters or partners?","volume":"81","author":"Kanekiyo","year":"2014","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"50380","DOI":"10.1074\/jbc.M204898200","article-title":"Apolipoprotein E4 forms a molten globule: A potential basis for its association with disease","volume":"277","author":"Morrow","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14813","DOI":"10.1073\/pnas.1106420108","article-title":"Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions","volume":"108","author":"Chen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0065-3233(08)60642-7","article-title":"Apolipoprotein E: Structure-function relationships","volume":"45","author":"Weisgraber","year":"1994","journal-title":"Adv. Protein Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0022-2275(20)32449-4","article-title":"Competition of A\u03b2 amyloid peptide and apolipoprotein E for receptor-mediated endocy-tosis","volume":"40","author":"Winkler","year":"1999","journal-title":"J. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1807","DOI":"10.1073\/pnas.1220484110","article-title":"Holtzman, D.M. ApoE influences amyloid-\u03b2 (A\u03b2) clearance despite minimal apoE\/A\u03b2 associa-tion in physiological conditions","volume":"110","author":"Verghese","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41774","DOI":"10.1074\/jbc.M112.407957","article-title":"APOE4-specific changes in A\u03b2 accumulation in a new transgenic mouse model of Alz-heimer disease","volume":"287","author":"Youmans","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1523\/JNEUROSCI.0887-09.2009","article-title":"Human APOE isoform-dependent effects on brain beta-amyloid levels in PDAPP transgenic mice","volume":"29","author":"Liu","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1523\/JNEUROSCI.5491-10.2011","article-title":"Heparan Sulphate Proteoglycan and the Low-Density Lipoprotein Receptor-Related Protein 1 Constitute Major Pathways for Neuronal Amyloid-\u03b2 Uptake","volume":"31","author":"Kanekiyo","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cui, H., Hung, A.C., Klaver, D.W., Suzuki, T., Freeman, C., Narkowicz, C., Jacobson, G.A., and Small, D.H. (2011). Effects of heparin and enoxaparin on APP processing and A\u03b2 production in primary corti-cal neurons from Tg2576 mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023007"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1042\/BST0331116","article-title":"Novel heparan sulphate analogues: Inhibition of beta-secretase cleavage of amyloid precursor protein","volume":"33","author":"Patey","year":"2005","journal-title":"Biochem. Soc. Trans."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1100\/tsw.2009.100","article-title":"Alzheimer\u2019s disease: Another target for heparin therapy","volume":"9","author":"Bergamaschini","year":"2009","journal-title":"Sci. World J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Andrade, S., Ramalho, M.J., Loureiro, J.A., and Pereira, M.D.C. (2019). Natural compounds for Alzheimer\u2019s disease therapy: A systematic review of preclinical and clinical studies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092313"},{"key":"ref_30","first-page":"1556","article-title":"Direct oral anticoagulants: A new therapy against Alzheimer\u2019s disease?","volume":"16","author":"Grossmann","year":"2021","journal-title":"NRR"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4634","DOI":"10.1038\/s41467-021-24900-4","article-title":"Endo-lysosomal A\u03b2 concentration and pH trigger formation of A\u03b2 oligomers that potently induce Tau missorting","volume":"12","author":"Hasecke","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neurobiolaging.2020.12.007","article-title":"Decreased pH in the aging brain and Alzheimer\u2019s disease","volume":"101","author":"Decker","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0006-8993(00)03322-9","article-title":"Acidic pH promotes the formation of toxic fibrils from \u03b2-amyloid peptide","volume":"893","author":"Su","year":"2001","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/ct100578z","article-title":"PROPKA3: Consistent treatment of internal and surface residues in empirical pKa predictions","volume":"7","author":"Olsson","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1021\/ct200133y","article-title":"Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values","volume":"7","author":"Olsson","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1002\/pro.3280","article-title":"Improvements to the APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2018","journal-title":"Protein Sci."},{"key":"ref_37","unstructured":"The UniProt Consortium (2021). UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res., 49, D480\u2013D489. Available online: https:\/\/www.uniprot.org\/uniprot\/P02649."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1021\/bi002417n","article-title":"Interaction of the N-terminal domain of apolipoprotein E4 with heparin","volume":"40","author":"Dong","year":"2001","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nprot.2010.5","article-title":"I-TASSER: A unified platform for automated protein structure and function prediction","volume":"5","author":"Roy","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nmeth.3213","article-title":"The I-TASSER Suite: Protein structure and function prediction","volume":"12","author":"Yang","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: New development for protein structure and function predictions","volume":"43","author":"Yang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5642","DOI":"10.1046\/j.1432-1033.2002.03271.x","article-title":"Solution structure of the Alzheimer amyloid \u03b2-peptide (1\u201342) in an apolar microenvi-ronment: Similarity with a virus fusion domain","volume":"269","author":"Crescenzi","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119145","DOI":"10.1016\/j.bbamcr.2021.119145","article-title":"Intracellular ion changes induced by the exposure to beta-amyloid can be explained by the for-mation of channels in the lysosomal membranes","volume":"1869","author":"Zaretsky","year":"2022","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"183506","DOI":"10.1016\/j.bbamem.2020.183506","article-title":"Flow cytometry method to quantify the formation of beta-amyloid membrane ion channels","volume":"1863","author":"Zaretsky","year":"2021","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_45","first-page":"1770627","article-title":"Molecular simulations of amyloid beta assemblies","volume":"5","author":"Grasso","year":"2020","journal-title":"Adv. Phys. X"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.bpj.2011.10.024","article-title":"Improving the physical realism and structural accuracy of protein models by a two-step atom-ic-level energy minimization","volume":"101","author":"Xu","year":"2011","journal-title":"Biophys. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/pro.3289","article-title":"PDBsum: Structural summaries of PDB entries","volume":"27","author":"Laskowski","year":"2018","journal-title":"Protein Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.nbd.2010.06.008","article-title":"Enoxaparin treatment administered at both early and late stages of amyloid \u03b2 deposition improves cognition of APPswe\/PS1dE9 mice with differential effects on brain A\u03b2 levels","volume":"40","author":"Timmer","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_49","unstructured":"Dennington, R., Keith, T.A., and Millam, J.M. (2016). GaussView 6.0. 16, Semichem Inc."},{"key":"ref_50","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16 Revision C01, Gaussian Inc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cplett.2004.06.011","article-title":"A new hybrid exchange-correlation functional using the Coulomb-attenuating method (CAM-B3LYP)","volume":"393","author":"Yanai","year":"2004","journal-title":"Chem. Phys. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5829","DOI":"10.1063\/1.467146","article-title":"Fully optimized contracted Gaussian basis sets of triple zeta valence quality for atoms Li to Kr","volume":"100","author":"Huber","year":"1994","journal-title":"J. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/BF00549096","article-title":"Bonded-atom fragments for describing molecular charge densities","volume":"44","author":"Hirshfeld","year":"1977","journal-title":"Theor. Chim. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1021\/ja00293a005","article-title":"Electron density distribution analysis for nitromethane, nitromethide, and nitramide","volume":"107","author":"Ritchie","year":"1985","journal-title":"J. Am. Chem. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/jcc.540080430","article-title":"Some methods and applications of electron density distribution analysis","volume":"8","author":"Ritchie","year":"1987","journal-title":"J. Comput. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6665","DOI":"10.1073\/pnas.0408037102","article-title":"Potential energy functions for atomic-level simulations of water and organic and biomolecular systems","volume":"102","author":"Jorgensen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3864","DOI":"10.1021\/acs.jpcb.7b00272","article-title":"1.14* CM1A-LBCC: Localized bond-charge corrected CM1A charges for condensed-phase simulations","volume":"121","author":"Dodda","year":"2017","journal-title":"Phys. Chem. B"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"W331","DOI":"10.1093\/nar\/gkx312","article-title":"LigParGen web server: An automatic OPLS-AA parameter generator for organic ligands","volume":"45","author":"Dodda","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6474","DOI":"10.1021\/jp003919d","article-title":"Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides","volume":"105","author":"Kaminski","year":"2001","journal-title":"J. Phys. Chem. B"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/3-540-45784-4_14","article-title":"Efficient unbound docking of rigid molecules","volume":"Volume 40","author":"Duhovny","year":"2002","journal-title":"International Workshop on Algorithms in Bioinformatics"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"W363","DOI":"10.1093\/nar\/gki481","article-title":"PatchDock and SymmDock: Servers for rigid and symmetric docking","volume":"33","author":"Inbar","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/prot.21495","article-title":"FireDock: Fast interaction refinement in molecular docking","volume":"69","author":"Andrusier","year":"2007","journal-title":"Proteins Struct. Funct. Bioinf."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gkn186","article-title":"FireDock: A web server for fast interaction refinement in molecular docking","volume":"36","author":"Mashiach","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1002\/jcc.26011","article-title":"More bang for your buck: Improved use of GPU nodes for GROMACS 2018","volume":"40","author":"Kutzner","year":"2019","journal-title":"J. Comput. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical sampling through velocity rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"075503","DOI":"10.1103\/PhysRevLett.90.075503","article-title":"Predicting crystal structures: The Parrinello-Rahman method revisited","volume":"90","author":"Laio","year":"2003","journal-title":"Phys. Rev. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_73","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_74","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1021\/ct700200b","article-title":"P-LINCS: A parallel linear constraint solver for molecular simulation","volume":"4","author":"Hess","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/minf.201100135","article-title":"Free energy calculations by the molecular mechanics Poisson-Boltzmann surface area method","volume":"31","author":"Homeyer","year":"2012","journal-title":"Mol. Inform."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1021\/jm801444x","article-title":"Large-scale application of high-throughput molecular mechanics with Poisson- Boltzmann sur-face area for routine physics-based scoring of protein-ligand complexes","volume":"52","author":"Brown","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/jcc.21372","article-title":"Fast and accurate predictions of binding free energies using MM-PBSA and MM-GBSA","volume":"31","author":"Rastelli","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_79","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_80","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_81","unstructured":"Schr\u00f6dinger, L., and DeLano, W. (2021, November 10). PyMOL. The PyMOL Molecular Graphics System, Version 2. Available online: https:\/\/pymol.org\/2\/."},{"key":"ref_82","unstructured":"Turner, P., and Grace, X. (2005). Version 5.1. 19. Center for Coastal and Land-Margin Research, Oregon Graduate Institute of Science and Technology."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/protein\/8.2.127","article-title":"LIGPLOT: A program to generate schematic diagrams of protein\u2013ligand interactions","volume":"8","author":"Wallace","year":"1995","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.181342398","article-title":"Electrostatics of nanosystems: Application to microtubules and the ribosome","volume":"98","author":"Baker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: An automated pipeline for the setup of Poisson\u2013Boltzmann electrostatics calcula-tions","volume":"32","author":"Dolinsky","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_86","unstructured":"WR Inc. (2020). Mathematica, Version 12.1, WR Inc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00401-013-1086-9","article-title":"Brain regional correlation of amyloid-\u03b2 with synapses and apolipoprotein E in non-demented individuals: Potential mechanisms underlying regional vulnerability to amy-loid-\u03b2 accumulation","volume":"125","author":"Shinohara","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1172\/JCI96429","article-title":"Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation","volume":"128","author":"Liao","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_89","unstructured":"(2021, April 10). Enoxaparin. (s.f.). NCBI. Retrieved 12 November 2021, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Heparin."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Gastegger, M., and Marquetand, P. (2020). Molecular dynamics with neural network potentials. arXiv.","DOI":"10.1007\/978-3-030-40245-7_12"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1021\/acs.jcim.8b00180","article-title":"Hydration free energies in the FreeSolv database calculated with polarized iterative Hirshfeld charges","volume":"58","author":"Riquelme","year":"2018","journal-title":"J. Chem. Inf. Model."},{"key":"ref_92","first-page":"100360","article-title":"Evaluation of vibrational, electronic, reactivity and bioactivity of propafenone\u2014A spectro-scopic, DFT and molecular docking approach","volume":"26","author":"George","year":"2020","journal-title":"Chem. Data Coll."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"130628","DOI":"10.1016\/j.molstruc.2021.130628","article-title":"Conformational search, structural analysis, vibrational properties, reactivity study and affinity towards DNA of the novel insecticide flonicamid","volume":"1241","author":"Corregidor","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.jmb.2019.04.019","article-title":"The molecular basis for apolipoprotein E4 as the major risk factor for late-onset Alzheimer\u2019s disease","volume":"431","author":"Raulin","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"S183","DOI":"10.1194\/jlr.R800069-JLR200","article-title":"Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer\u2019s disease to AIDS","volume":"50","author":"Mahley","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1016\/j.bpj.2017.10.006","article-title":"tomistic insights into structural differences between E3 and E4 isoforms of apolipoprotein E","volume":"113","author":"Ray","year":"2017","journal-title":"Biophys. J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"225101","DOI":"10.1063\/1.5096379","article-title":"Aggregation rate of amyloid beta peptide is controlled by beta-content in monomeric state","volume":"150","author":"Thu","year":"2019","journal-title":"J. Chem. Phys."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1139\/cjc-2016-0267","article-title":"Molecular dynamics studies of a \u03b2-sheet blocking peptide with the full-length amyloid beta peptide of Alzheimer\u2019s disease","volume":"94","author":"Amini","year":"2016","journal-title":"Can. J. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.str.2010.08.009","article-title":"Biology of amyloid: Structure, function, and regulation","volume":"18","author":"Greenwald","year":"2010","journal-title":"Structure"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1146\/annurev-biochem-090908-120656","article-title":"Amyloid structure: Conformational diversity and consequences","volume":"80","author":"Toyama","year":"2011","journal-title":"Annu. Rev. Biochem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.sbi.2019.09.001","article-title":"Amyloid structures: Much more than just a cross-\u03b2 fold","volume":"60","author":"Gallardo","year":"2020","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"66391","DOI":"10.1039\/C5RA12328C","article-title":"The mechanisms of flavonoids inhibiting conformational transition of amyloid-\u03b2 42 monomer: A comparative molecular dynamics simulation study","volume":"5","author":"Wang","year":"2015","journal-title":"RSC Adv."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.bpj.2016.08.001","article-title":"Molecular dynamics simulations of amyloid \u03b2-peptide (1\u201342): Tetramer formation and membrane interactions","volume":"111","author":"Brown","year":"2016","journal-title":"Biophys. J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1021\/acschemneuro.6b00375","article-title":"Tautomeric effect of histidine on the monomeric structure of amyloid \u03b2-peptide (1\u201342)","volume":"8","author":"Shi","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1080\/07391102.2019.1632225","article-title":"Edaravone inhibits the conformational transition of amyloid-\u03b242: Insights from molecu-lar dynamics simulations","volume":"38","author":"Liu","year":"2019","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"135103","DOI":"10.1063\/1.4979516","article-title":"Cooperative structural transitions in amyloid-like aggregation","volume":"146","author":"Steckmann","year":"2017","journal-title":"J. Chem. Phys."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade","volume":"86","author":"Chiti","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"10602","DOI":"10.1074\/jbc.271.18.10602","article-title":"The Interaction between Apolipoprotein E and Alzheimer\u2019s Amyloid \u03b2-Peptide Is De-pendent on \u03b2-Peptide Conformation","volume":"271","author":"Golabek","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"14782","DOI":"10.1074\/jbc.M213207200","article-title":"Characterization of the heparin binding sites in human apolipoprotein E","volume":"278","author":"Saito","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Luo, J., Mar\u00e9chal, J.D., W\u00e4rml\u00e4nder, S., Gr\u00e4slund, A., and Per\u00e1lvarez-Mar\u0131n, A. (2010). In Silico Analysis of the Apolipoprotein E and the Amyloid b Peptide. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000663"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5026","DOI":"10.1080\/07391102.2020.1784287","article-title":"Alzheimer\u2019s disease: Unraveling APOE4 binding to amyloid-beta peptide and lipids with mo-lecular dynamics and quantum mechanics","volume":"39","author":"Gillet","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.ajpath.2013.01.034","article-title":"Blocking the interaction between apolipoprotein E and A\u03b2 reduces intraneuronal accumu-lation of A\u03b2 and inhibits synaptic degeneration","volume":"182","author":"Kuszczyk","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1096\/fj.10-175976","article-title":"High ability of apolipoprotein E4 to stabilize amyloid-\u03b2 peptide oligomers, the patholog-ical entities responsible for Alzheimer\u2019s disease","volume":"25","author":"Cerf","year":"2011","journal-title":"FASEB J."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"15181","DOI":"10.1523\/JNEUROSCI.1542-12.2012","article-title":"Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid \u03b2 peptide","volume":"32","author":"Hashimoto","year":"2012","journal-title":"J. Neurosci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/4\/499\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:43:17Z","timestamp":1760136197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/4\/499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":114,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["biom12040499"],"URL":"https:\/\/doi.org\/10.3390\/biom12040499","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]}}}