pH-dependent interactions of coacervate-forming histidine-rich peptide with model lipid membranes

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dc.contributor.authorGudler, Sen_AU
dc.contributor.authorFerreira, FVen_AU
dc.contributor.authorTing, JSMen_AU
dc.contributor.authorDomene, Cen_AU
dc.contributor.authorMaricar, Sen_AU
dc.contributor.authorLe Brun, APen_AU
dc.contributor.authorYepuri, NRen_AU
dc.contributor.authorMoir, Men_AU
dc.contributor.authorRussell, RAen_AU
dc.contributor.authorDarwish, TAen_AU
dc.contributor.authorMiserez, Aen_AU
dc.contributor.authorCárdenas, Men_AU
dc.date.accessioned2024-02-28T00:31:35Zen_AU
dc.date.available2024-02-28T00:31:35Zen_AU
dc.date.issued2024-01-19en_AU
dc.date.statistics2024-02-27en_AU
dc.descriptionThis article is part of the Research Topic: 1st Galapagos Soft Matter Conference - Research Topicen_AU
dc.description.abstractPeptide-based liquid droplets (coacervates) produced by spontaneous liquid-liquid phase separation (LLPS), have emerged as a promising class of drug delivery systems due to their high entrapping efficiency and the simplicity of their formulation. However, the detailed mechanisms governing their interaction with cell membranes and cellular uptake remain poorly understood. In this study, we investigated the interactions of peptide coacervates composed of HBpep—peptide derived from the histidine-rich beak proteins (HBPs) of the Humboldt squid—with model cellular membranes in the form of supported lipid bilayers (SLBs). We employed quartz crystal microbalance with dissipation monitoring (QCM-D), neutron reflectometry (NR) and atomistic molecular dynamics (MD) simulations to reveal the nature of these interactions in the absence of fluorescent labels or tags. HBpep forms small oligomers at pH 6 whereas it forms µm-sized coacervates at physiological pH. Our findings reveal that both HBpep oligomers and HBpep-coacervates adsorb onto SLBs at pH 6 and 7.4, respectively. At pH 6, when the peptide carries a net positive charge, HBpep oligomers insert into the SLB, facilitated by the peptide’s interactions with the charged lipids and cholesterol. Importantly, however, HBpep coacervate adsorption at physiological pH, when it is largely uncharged, is fully reversible, suggesting no significant lipid bilayer rearrangement. HBpep coacervates, previously identified as efficient drug delivery vehicles, do not interact with the lipid membrane in the same manner as traditional cationic drug delivery systems or cell-penetrating peptides. Based on our findings, HBpep coacervates at physiological pH cannot cross the cell membrane by a simple passive mechanism and are thus likely to adopt a non-canonical cell entry pathway. ©2024 Gudlur, Ferreira, Ting, Domene, Maricar, Le Brun, Yepuri, Moir, Russell, Darwish, Miserez and Cárdenas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).en_AU
dc.description.sponsorshipWe thank the NTU Optical Bio-Imaging Centre (NOBIC) at the Singapore Centre for Environmental Life Sciences Engineering (SCELSE), NTU for the use of DIC microscopes and Dr. Yong Hwee Foo for his help and suggestions with imaging. This research was undertaken on the SPATZ beamline at the Australian Centre for Neutron Scattering, part of ANSTO. We are thankful to ANSTO for this opportunity and for allowing us to use their facilities. CD acknowledges use of computing resources on HPC platforms granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://hecbiosim.ac.uk), supported by EPSRC (Grant No. EP/R029407/1). MC thanks the Swedish Research Council, Biofilm—Research center for Biointerfaces, and Wennergren foundation for funding.en_AU
dc.identifier.articlenumber1339496en_AU
dc.identifier.citationGudlur, S., Ferreira, F. V., Ting, J. S. M., Domene, C., Maricar, S., Le Brun, A. P., Yepuri, N., Moir, M., Russell, R., Darwish, T., Miserez, A., & Cárdenas, M. (2024). pH-dependent interactions of coacervate-forming histidine-rich peptide with model lipid membranes. Frontiers in Soft Matter, 3, 1339496. doi:10.3389/frsfm.2023.1339496en_AU
dc.identifier.issn2813-0499en_AU
dc.identifier.journaltitleFrontiers in Soft Matteren_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15463en_AU
dc.identifier.volume3en_AU
dc.language.isoenen_AU
dc.publisherFrontiers Mediaen_AU
dc.relation.urihttps://doi.org/10.3389/frsfm.2023.1339496en_AU
dc.subjectInteractionsen_AU
dc.subjectHistidineen_AU
dc.subjectPeptidesen_AU
dc.subjectLipidsen_AU
dc.subjectMembranesen_AU
dc.subjectPolymersen_AU
dc.subjectDrug deliveryen_AU
dc.subjectNeutron reflectorsen_AU
dc.titlepH-dependent interactions of coacervate-forming histidine-rich peptide with model lipid membranesen_AU
dc.typeJournal Articleen_AU
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