The α-Helical (AH) domain of the hepatitis C virus nonstructural protein NS5A – anchored at the cytoplasmic leaflet of the endoplamic reticulum – plays a role in viral replication but the peptides derived from the domain also exhibit remarkably broadspectrum virocidal activity raising questions about their modes of membrane association. Here, using giant lipid vesicles, we show that the AH peptide discriminates between membrane compositions: In cholesterol-containing membranes, peptide binding induces micro-domain formation. By contrast, cholesterol-depleted membranes undergo global softening at elevated peptide concentrations. Furthermore, in mixed populations, the presence of ~100 nanometer vesicles of viral dimensions suppress these peptide-induced perturbations in GUVs suggesting size-dependent membrane association. These synergistic – composition- and size-dependent –interactions explain, in part, how AH domain might on the one hand segregate molecules needed for viral assembly and furnish peptides exhibiting broad-spectrum virocidal activity on the other. Work done in partnership with: Seyed R. Tabaei1,2, Joshua Jackman1,2, Min-Chul Kim1,2, Darryl Y. Sasaki3, Jay T. Groves4, Bo Liedberg1,2, and Nam-Joon Cho*1,2,5 1Centre for Biomimetic Sensor Science, Nanyang Technological University, 50 Nanyang Drive 637553, Singapore 2School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Ave 637459, Singapore 3Biotechnology and Bioengineering Dept., Sandia National Laboratories, Livermore, California 94551 USA 4Chemistry Department, University of California, Berkeley, California 94720 USA and Mechanobiology Institute, National University of Singapore, Singapore 117411 5School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive 637459, Singapore

Cholesterol-enriched microdomain formation induced by viral-encoded, membrane active amphipathic peptide

251st National Meeting (2016)

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