Abstract
Membrane fusion is a crucial step in flavivirus infections and a potential target for antiviral strategies. Lipids and proteins play cooperative roles in the fusion process, which is triggered by the acidic pH inside the endosome. This acidic environment induces many changes in glycoprotein conformation and allows the action of a highly conserved hydrophobic sequence, the fusion peptide (FP). Despite the large volume of information available on the virus-triggered fusion process, little is known regarding the mechanisms behind flavivirus–cell membrane fusion. Here, we evaluated the contribution of a natural single amino acid difference on two flavivirus FPs, FLAG (98DRGWGNGCGLFGK110) and FLAH (98DRGWGNHCGLFGK110), and investigated the role of the charge of the target membrane on the fusion process. We used an in silico approach to simulate the interaction of the FPs with a lipid bilayer in a complementary way and used spectroscopic approaches to collect conformation information. We found that both peptides interact with neutral and anionic micelles, and molecular dynamics (MD) simulations showed the interaction of the FPs with the lipid bilayer. The participation of the indole ring of Trp appeared to be important for the anchoring of both peptides in the membrane model, as indicated by MD simulations and spectroscopic analyses. Mild differences between FLAG and FLAH were observed according to the pH and the charge of the target membrane model. The MD simulations of the membrane showed that both peptides adopted a bend structure, and an interaction between the aromatic residues was strongly suggested, which was also observed by circular dichroism in the presence of micelles. As the FPs of viral fusion proteins play a key role in the mechanism of viral fusion, understanding the interactions between peptides and membranes is crucial for medical science and biology and may contribute to the design of new antiviral drugs.
Highlights
Enveloped viruses usually enter host cells through membrane fusion mediated by a viral glycoprotein that protrudes through the viral envelope [1]
We evaluated the contribution of a single amino acid difference on two flavivirus fusion peptides and the importance of the target membrane charge to the fusion process
We found that both peptides interacted with different membrane models at the water–membrane interface and adopted a bent structure
Summary
Enveloped viruses usually enter host cells through membrane fusion mediated by a viral glycoprotein that protrudes through the viral envelope [1]. Fusion proteins are present in the envelope as E-E homodimers that dissociate and form highly stable homotrimers after exposure to endocytic low pH, which is needed for fusion [14] This conformational change exposes the FP, allowing the protein to interact with the membrane and destabilize it. We used an in silico approach to simulate the interaction of FPs with a lipid bilayer in a complementary way with spectroscopic approaches to collect molecular parameters and conformational information. These data provide us new insights into the flavivirus fusion peptides– membrane interaction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
