{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:43:35Z","timestamp":1792784615984,"version":"4.5.0"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2027,8,17]],"date-time":"2027-08-17T00:00:00Z","timestamp":1818460800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG, Germany)","award":["469240103"],"award-info":[{"award-number":["469240103"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, Germany)","award":["567384216"],"award-info":[{"award-number":["567384216"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Heparin, a highly sulfated glycosaminoglycan, interacts with numerous proteins through electrostatic and multivalent binding mechanisms. In the context of SARS-CoV-2 infection, platelet factor 4 (PF4) has been proposed to form complexes with the viral spike protein (S protein), potentially contributing to immune-mediated thrombotic complications. However, the molecular mechanisms by which heparin modulates PF4-S protein interactions remain poorly understood. Here, we investigate how unfractionated heparin (UFH) influences the formation and stability of PF4-S protein complexes using a combination of ensemble binding assays, single-molecule force spectroscopy, and molecular dynamics simulations. ELISA measurements reveal concentration-dependent and partner-specific effects of UFH on S protein interactions. While low concentrations of UFH enhance ACE2-S protein binding, higher concentrations produce a modest reduction, indicating biphasic modulation of receptor engagement. In contrast, UFH inhibits PF4-S protein binding at low to intermediate concentrations, with partial restoration at higher levels. Single-molecule force spectroscopy confirms that UFH decreases the mechanical stability of the PF4-S protein complex, as reflected by reduced unbinding forces that reach saturation at concentrations \u22655 IU mL\u22121. Molecular dynamics simulations using the dp5 heparin fragment demonstrate energetically favorable binding to both PF4 and the S1 subunit of the S protein. In ternary S1-PF4-dp5 assemblies, heparin alters interfacial contacts and reshapes the energetic landscape of the protein-protein interaction, suggesting modulation through electrostatic reorganization and interfacial remodeling. These findings provide mechanistic insight into glycosaminoglycan-mediated regulation of PF4-S protein complexes and highlight how heparin can modulate biomacromolecular interactions at viral-host protein interfaces.<\/jats:p>","DOI":"10.1021\/acsabm.6c00502","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:02:01Z","timestamp":1787007721000},"page":"7999-8012","source":"Crossref","is-referenced-by-count":0,"title":["Heparin Modulates SARS-CoV-2 Spike\u2212Platelet Factor 4 Interactions through Concentration-Dependent Interface Remodeling"],"prefix":"10.1021","volume":"9","author":[{"given":"Dayamai Sai","family":"Satram","sequence":"first","affiliation":[{"name":"Institute for Bioprocessing and Analytical Measurement Techniques (iba) , ,","place":["Heilbad Heiligenstadt, Germany, 37308"]},{"name":"Martin Luther University of Halle-Wittenberg , , ,","place":["Halle, Germany, 06108"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute for Bioprocessing and Analytical Measurement Techniques (iba) , ,","place":["Heilbad Heiligenstadt, Germany, 37308"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0510-5605","authenticated-orcid":true,"given":"Thi H.","family":"Ho","sequence":"additional","affiliation":[{"name":"Van Lang University , , ,","place":["Ho Chi Minh City, Vietnam, 700000"]},{"name":"Van Lang University , , ,","place":["Ho Chi Minh City, Vietnam, 700000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Heinrich","sequence":"additional","affiliation":[{"name":"Institute for Bioprocessing and Analytical Measurement Techniques (iba) , ,","place":["Heilbad Heiligenstadt, Germany, 37308"]},{"name":"Technische Universit\u00e4t Ilmenau , , ,","place":["Ilmenau, Germany, 98694"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1721-6786","authenticated-orcid":true,"given":"Thuat T.","family":"Trinh","sequence":"additional","affiliation":[{"name":"Norwegian University of Science and Technology , , ,","place":["Trondheim, Norway, 7491"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9237-3482","authenticated-orcid":true,"given":"Thi-Huong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Institute for Bioprocessing and Analytical Measurement Techniques (iba) , ,","place":["Heilbad Heiligenstadt, Germany, 37308"]},{"name":"Technische Universit\u00e4t Ilmenau , , ,","place":["Ilmenau, Germany, 98694"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"issue":"6516","key":"2026092215063293100_cit1","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1101\/2020.05.21.109322","article-title":"The emergence of SARS-CoV-2 in Europe and North America","volume":"370","author":"Worobey","year":"2020","journal-title":"Science"},{"issue":"1","key":"2026092215063293100_cit2","doi-asserted-by":"publisher","first-page":"157","DOI":"10.23750\/abm.v91i1.9397","article-title":"WHO Declares COVID-19 a Pandemic","volume":"91","author":"Cucinotta","year":"2020","journal-title":"Acta Biomed."},{"key":"2026092215063293100_cit3","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.928996","article-title":"Long-Term Respiratory and Neurological Sequelae of COVID-19","volume":"26","author":"Wang","year":"2020","journal-title":"Med. 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