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Here, we investigate heparin-induced aggregation of bovine serum albumin (BSA) using different spectroscopic techniques [absorption, 8-anilino-1-naphthalene sulfonic acid (ANS) and thioflavin T (ThT) fluorescence binding, and far- and near-UV circular dichroism]. Kinetic measurements revealed that heparin is involved in the significant enhancement of aggregation of BSA. The outcomes showed dearth of the lag phase and a considerable change in rate constant, which provides conclusive evidence, that is, heparin-induced BSA aggregation involves the pathway of the downhill polymerization mechanism. Heparin also causes enhancement of fluorescence intensity of BSA significantly. Moreover, heparin was observed to form amyloids and amorphous aggregates of BSA which were confirmed by ThT and ANS fluorescence, respectively. Circular dichroism measurements exhibit a considerable change in the secondary and tertiary structure of the protein due to heparin. In addition, binding studies of heparin with BSA to know the cause of aggregation, isothermal titration calorimetry measurements were exploited, from which heparin was observed to promote the aggregation of BSA by virtue of electrostatic interactions between positively charged amino acid residues of protein and negatively charged groups of GAG. The nature of binding of heparin with BSA is very much apparent with an appreciable heat of interaction and is largely exothermic in nature. Moreover, the Gibbs free energy change (\u0394G) is negative, which indicates spontaneous nature of binding, and the enthalpy change (\u0394H) and entropy change (\u0394S) are also largely negative, which suggest that the interaction is driven by hydrogen bonding.<\/jats:p>","DOI":"10.1021\/acsomega.0c05638","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T22:03:20Z","timestamp":1610661800000},"page":"2328-2339","source":"Crossref","is-referenced-by-count":49,"title":["Heparin Accelerates the Protein Aggregation via the\nDownhill Polymerization Mechanism: Multi-Spectroscopic Studies to\nDelineate the Implications on Proteinopathies"],"prefix":"10.1021","volume":"6","author":[{"given":"Ishfaq Ahmad","family":"Ahanger","sequence":"first","affiliation":[{"name":"Amity University Haryana , , ,","place":["Gurugram, India, 122 413"]},{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5998-7100","authenticated-orcid":true,"given":"Zahoor Ahmad","family":"Parray","sequence":"additional","affiliation":[{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalida","family":"Nasreen","sequence":"additional","affiliation":[{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faizan","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3663-4940","authenticated-orcid":true,"given":"Md. Imtaiyaz","family":"Hassan","sequence":"additional","affiliation":[{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9060-7970","authenticated-orcid":true,"given":"Asimul","family":"Islam","sequence":"additional","affiliation":[{"name":"Jamia Millia Islamia , , Jamia Nagar , ,","place":["New Delhi, India, 110025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anurag","family":"Sharma","sequence":"additional","affiliation":[{"name":"Amity University Haryana , , ,","place":["Gurugram, India, 122 413"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"key":"2026090210224763000_cit1","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.carres.2014.06.023","article-title":"Re-visiting\nthe structure of heparin","volume":"403","author":"Casu","year":"2015","journal-title":"Carbohydr. Res."},{"key":"2026090210224763000_cit2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/978-3-642-23056-1_8","article-title":"Heparin and Heparan\nSulfate: Analyzing Structure and Microheterogeneity","volume-title":"Heparin\u2500A Century of Progress. Handbook of Experimental\nPharmacology","author":"Shriver","year":"2012"},{"key":"2026090210224763000_cit3","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1046\/j.1432-1327.1999.00957.x","article-title":"Interactions\nof Alzheimer amyloid-\u03b2 peptides with glycosaminoglycans","volume":"266","author":"McLaurin","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"2026090210224763000_cit4","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1002\/pro.3149","article-title":"Heparin-induced amyloid\nfibrillation of \u03b22-microglobulin explained by solubility and\na supersaturation-dependent conformational phase diagram","volume":"26","author":"So","year":"2017","journal-title":"Protein Sci."},{"key":"2026090210224763000_cit5","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1021\/bi011711s","article-title":"Heparin and Other Glycosaminoglycans\nStimulate the Formation of Amyloid Fibrils from \u03b1-Synuclein\nin Vitro","volume":"41","author":"Cohlberg","year":"2002","journal-title":"Biochemistry"},{"key":"2026090210224763000_cit6","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/s0024-3795(00)00095-1","article-title":"Identification\nof almost invariant aggregates in reversible nearly uncoupled Markov\nchains","volume":"315","author":"Deuflhard","year":"2000","journal-title":"Lin. Algebra Appl."},{"key":"2026090210224763000_cit7","doi-asserted-by":"publisher","first-page":"a004507","DOI":"10.1101\/cshperspect.a004507","article-title":"Chemical and Biological Approaches\nfor Adapting Proteostasis\nto Ameliorate Protein Misfolding and Aggregation Diseases\u2500Progress\nand Prognosis","volume":"3","author":"Lindquist","year":"2011","journal-title":"Cold Spring Harbor Perspect.\nBiol."},{"key":"2026090210224763000_cit8","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.brainres.2012.01.016","article-title":"The tip of\nthe iceberg: RNA-binding\nproteins with prion-like domains in neurodegenerative disease","volume":"1462","author":"King","year":"2012","journal-title":"Brain Res."},{"key":"2026090210224763000_cit9","first-page":"1","volume-title":"The Role of Heparin in\nthe Prion Proteins Aggregation","author":"Zhang","year":"2012"},{"key":"2026090210224763000_cit10","doi-asserted-by":"publisher","first-page":"5584","DOI":"10.1073\/pnas.1101194108","article-title":"Heparan sulfate\/heparin promotes\ntransthyretin fibrillization through selective binding to a basic\nmotif in the protein","volume":"108","author":"Noborn","year":"2011","journal-title":"Proc. Natl. Acad. Sci.\nU.S.A."},{"key":"2026090210224763000_cit11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022076","article-title":"Heparin Induces\nHarmless Fibril Formation\nin Amyloidogenic W7FW14F Apomyoglobin and Amyloid Aggregation in Wild-Type\nProtein In Vitro","volume":"6","author":"Vilasi","year":"2011","journal-title":"PLoS One"},{"key":"2026090210224763000_cit12","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1021\/bi0519295","article-title":"Heparin\nAccelerates Gelsolin Amyloidogenesis","volume":"45","author":"Suk","year":"2006","journal-title":"Biochemistry"},{"key":"2026090210224763000_cit13","doi-asserted-by":"publisher","first-page":"3436","DOI":"10.1096\/fj.09-134981","article-title":"Heparan sulfate promotes the aggregation\nof HDL-associated serum amyloid A: evidence for a proamyloidogenic\nhistidine molecular switch","volume":"23","author":"Elimova","year":"2009","journal-title":"FASEB J."},{"key":"2026090210224763000_cit14","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/s1474-4422(03)00484-8","article-title":"Heparan sulphate proteoglycans in\nAlzheimer\u2019s disease and amyloid-related disorders","volume":"2","author":"van Horssen","year":"2003","journal-title":"Lancet Neurol."},{"key":"2026090210224763000_cit15","first-page":"951","article-title":"Localization\nof the basement membrane heparan sulfate proteoglycan in islet amyloid\ndeposits in type II diabetes mellitus","volume":"116","author":"Young","year":"1992","journal-title":"Arch.\nPathol. Lab. Med."},{"key":"2026090210224763000_cit16","first-page":"601","article-title":"Immunolocalization of heparan sulfate\nproteoglycans to the prion protein amyloid plaques of Gerstmann-Straussler\nsyndrome, Creutzfeldt-Jakob disease and scrapie","volume":"63","author":"Snow","year":"1990","journal-title":"Lab. Invest."},{"key":"2026090210224763000_cit17","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.jcis.2009.12.012","article-title":"Characterization\nof different conformations\nof bovine serum albumin and their propensity to aggregate in the presence\nof N-cetyl-N,N,N-trimethyl ammonium bromide","volume":"343","author":"Sharma","year":"2010","journal-title":"J. Colloid Interface Sci."},{"key":"2026090210224763000_cit18","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1055\/s-1999-13990","article-title":"Heparinoids: structure,\nbiological activities and therapeutic\napplications","volume":"65","author":"Gunay","year":"1999","journal-title":"Planta Med."},{"key":"2026090210224763000_cit19","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1080\/19336918.2020.1767489","article-title":"The anti-cancer\nproperties of heparin and its derivatives: a review and prospect","volume":"14","author":"Ma","year":"2020","journal-title":"Cell Adhes. Migr."},{"key":"2026090210224763000_cit20","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding,\nfunctional amyloid, and human disease","volume":"75","author":"Chiti","year":"2006","journal-title":"Annu.\nRev. 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Biophys.\nActa"},{"key":"2026090210224763000_cit29","doi-asserted-by":"publisher","first-page":"3010","DOI":"10.1109\/tie.2009.2037644","article-title":"Real-time\nsimulation of grid-connected\nwind farms using physical aggregation","volume":"57","author":"Jalili-Marandi","year":"2010","journal-title":"IEEE\nTrans. Ind. Electron."},{"key":"2026090210224763000_cit30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmolb.2014.00001","article-title":"Recent and\nfuture grand challenges in protein folding, misfolding, and degradation","volume":"1","author":"Goloubinoff","year":"2014","journal-title":"Front. Mol. Biosci."},{"key":"2026090210224763000_cit31","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1016\/j.semcdb.2011.03.011","article-title":"Amyloid in neurodegenerative\ndiseases: friend or foe?","volume":"22","author":"Wolfe","year":"2011","journal-title":"Semin. Cell Dev. Biol."},{"key":"2026090210224763000_cit32","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s0065-3233(08)60640-3","article-title":"Structure of Serum\nAlbumin","volume":"45","author":"Carter","year":"1994","journal-title":"Adv. Protein Chem."},{"key":"2026090210224763000_cit33","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1080\/01932699908943842","article-title":"Effect of surfactants on the prevention\nof protein\naggregation during unfolding and refolding processes - Comparison\nwith molecular chaperone alpha-crystallin","volume":"20","author":"Bhattacharyya","year":"1999","journal-title":"J.\nDispersion Sci. Technol."},{"key":"2026090210224763000_cit34","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/1357-2725(96)00044-1","article-title":"Mechanism of denaturation of bovine serum albumin by\ndodecyl trimethylammonium bromide","volume":"28","author":"Moosavi-Movahedi","year":"1996","journal-title":"Int. J. Biochem.\nCell Biol."},{"key":"2026090210224763000_cit35","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1038\/sj.cdd.4400432","article-title":"Fatal attractions:\nabnormal protein aggregation and neuron death in Parkinson\u2019s\ndisease and Lewy body dementia","volume":"5","author":"Trojanowski","year":"1998","journal-title":"Cell Death Differ."},{"key":"2026090210224763000_cit36","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1016\/s1386-1425(00)00313-9","article-title":"Spectroscopic studies on the interaction of bovine (BSA) and human\n(HSA) serum albumins with ionic surfactants","volume":"56","author":"Gelamo","year":"2000","journal-title":"Spectrochim. Acta, Part A"},{"key":"2026090210224763000_cit37","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1016\/j.ijbiomac.2018.12.170","article-title":"First evidence\nof formation of pre-molten globule state in myoglobin: A macromolecular\ncrowding approach towards protein folding in vivo","volume":"126","author":"Parray","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"2026090210224763000_cit38","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/0076-6879(86)30013-2","article-title":"Calculation of protein conformation\nfrom circular dichroism","volume":"130","author":"Yang","year":"1986","journal-title":"Methods Enzymol."},{"key":"2026090210224763000_cit39","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1016\/j.bbapap.2014.10.001","volume":"1844","author":"Wei","year":"2014","journal-title":"Biochim. Biophys. 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J."},{"key":"2026090210224763000_cit43","doi-asserted-by":"publisher","first-page":"5988","DOI":"10.1021\/bi00017a028","article-title":"Thermodynamic\nstudies of the core histones: ionic strength and pH dependence of\nH2A-H2B dimer stability","volume":"34","author":"Karantza","year":"1995","journal-title":"Biochemistry"},{"key":"2026090210224763000_cit44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0153495","article-title":"Kinetics of thermal\ndenaturation and aggregation of bovine serum albumin","volume":"11","author":"Borzova","year":"2016","journal-title":"PLoS One"},{"key":"2026090210224763000_cit45","doi-asserted-by":"publisher","first-page":"3590","DOI":"10.1073\/pnas.96.7.3590","article-title":"Designing conditions for in vitro\nformation of amyloid protofilaments and fibrils","volume":"96","author":"Chiti","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090210224763000_cit46","doi-asserted-by":"publisher","first-page":"2353","DOI":"10.1016\/j.bpj.2008.12.3901","article-title":"Existence of different structural\nintermediates on the fibrillation pathway of human serum albumin","volume":"96","author":"Jua\u0301rez","year":"2009","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2026090210224763000_cit47","doi-asserted-by":"publisher","first-page":"5150","DOI":"10.1039\/c3cp54941k","article-title":"Hydrophobicity alone can not trigger aggregation in\nprotonated mammalian serum albumins","volume":"16","author":"Khan","year":"2014","journal-title":"Phys. Chem.\nChem. Phys."},{"key":"2026090210224763000_cit48","doi-asserted-by":"publisher","first-page":"42233","DOI":"10.1074\/jbc.m112.396416","article-title":"S100A6\namyloid fibril\nformation is calcium-modulated and enhances superoxide dismutase-1\n(SOD1) aggregation","volume":"287","author":"Botelho","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026090210224763000_cit49","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0172208","article-title":"Selective inhibition of aggregation\/fibrillation\nof\nbovine serum albumin by osmolytes: Mechanistic and energetics insights","volume":"12","author":"Dasgupta","year":"2017","journal-title":"PLoS One"},{"key":"2026090210224763000_cit50","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.chembiol.2014.03.014","article-title":"Direct Observations of Amyloid \u03b2 Self-Assembly\nin Live Cells Provide Insights into Differences in the Kinetics of\nA\u03b2(1-40) and A\u03b2(1-42) Aggregation","volume":"21","author":"Esbjo\u0308rner","year":"2014","journal-title":"Chem. Biol."},{"key":"2026090210224763000_cit51","doi-asserted-by":"publisher","first-page":"7365","DOI":"10.1021\/bi049621l","article-title":"Transthyretin Aggregation\nunder Partially Denaturing Conditions Is a Downhill Polymerization","volume":"43","author":"Hurshman","year":"2004","journal-title":"Biochemistry"},{"key":"2026090210224763000_cit52","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s11095-012-0885-3","article-title":"Aggregation\nmechanism of an IgG2\nand two IgG1 monoclonal antibodies at low pH: from oligomers to larger\naggregates","volume":"30","author":"Arosio","year":"2013","journal-title":"Pharm. Res."},{"key":"2026090210224763000_cit53","doi-asserted-by":"publisher","first-page":"3129","DOI":"10.1110\/ps.051692305","article-title":"The kinetic behavior of insulin fibrillation\nis determined\nby heterogeneous nucleation pathways","volume":"14","author":"Librizzi","year":"2005","journal-title":"Protein\nSci."},{"key":"2026090210224763000_cit54","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.bbapap.2008.10.016","article-title":"Protein\naggregation kinetics, mechanism,\nand curve-fitting: a review of the literature","volume":"1794","author":"Morris","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090210224763000_cit55","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1016\/j.bbapap.2007.06.008","article-title":"Aggregation\nand fibrillation of bovine serum albumin","volume":"1774","author":"Holm","year":"2007","journal-title":"Biochim.\nBiophys. 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