The Structural Dynamics of the Flavivirus Fusion Peptide–Membrane Interaction

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.

The three lives of viral fusion peptides

“…This is because the globular structures of the FL-containing DII-s behave as rigid bodies along the fusion pathway, i.e., they do not undergo significant structural rearrangements during the process besides their spatial reorientation. It is thus inferred that, in contrast to Class I internal FPs, short Class II FLs would retain their short-loop conformation upon insertion into the target membrane, an assumption supported by structural studies based on synthetic sequences (Melo et al, 2009;Mendes et al, 2012;Mohanram et al, 2012).…”

Bacteria on steroids: the enzymatic mechanism of an NADH-dependent dehydrogenase that regulates the conversion of cortisol to androgen in the gut microbiome

“…Hybrid QM/MM has been the main tool used to study processes that cannot be explained by classical MM methods alone (43,67,68). In biological contexts, QM/MM calculations are often used in enzymology (69,70) as well as to investigate polarizable molecules in different environments (71,72). In the QM/MM molecular dynamics (MD) approach, the system of interest is typically investigated in a water bath ( Fig.…”

Study of the mechanism of protonated histidine-induced conformational changes in the Zika virus dimeric envelope protein using accelerated molecular dynamic simulations

“…Over the last decade, pH-introduced conformational changes in flaviviruses, especially DENV, were extensively explored using experimental and computational methods [30][31][32][33][34][35][36][37]. The X-ray crystal structures of TBEV, WNV, JEV and DENV confirmed that the mature E protein can adopt different conformations under neutral and low pH conditions [16,26,[38][39][40][41][42].…”