Among lipid-enveloped viruses that pose a global health threat, human parainfluenza virus type 3 (HPIV3) is a major cause of severe respiratory illness in young children, accounting for 5%–6% of respiratory infections worldwide. Despite its impact, there are currently no vaccines or antiviral treatments available. HPIV3 enters host cells through fusion of its lipid envelope with the host membrane, mediated by the conserved fusion peptide (FP) in the viral F protein. The FP is released during the F protein's transition from a prefusion to extended conformation and inserts into the host membrane to drive fusion. However, the mechanism by which the FP disrupts the host membrane to promote fusion remains unclear. Understanding this is essential for assessing its role in the steps leading to fusion. To investigate this, we used molecular dynamics simulations to test how different FP orientations and oligomerization states influence membrane disruption, specifically membrane curvature. We tested three hypotheses regarding the mechanical role of the FP in inducing host membrane curvature: (1) deep parallel insertion inducing negative curvature in the extracellular leaflet, (2) shallow parallel insertion causing positive curvature, and (3) transmembrane (TM) insertion generating negative curvature in the cytoplasmic leaflet. Our results show that FP oligomerization and orientation influence membrane curvature, with the TM trimer causing more positive curvature than the TM monomer or parallel monomer configurations. These findings support the idea that FP oligomerization increases membrane curvature. Additionally, this work provides new insights into the mechanical role of the HPIV3 FP, showing how its structural states modulate membrane curvature, lowering the energetic barriers to viral fusion.
Brunet et al. (Sun,) studied this question.