Different Binding Modes of SARS-CoV-1 and SARS-CoV-2 Fusion Peptides to Cell Membranes: The Influence of Peptide Helix Length

Abstract

Although the amino acid sequences of SARS-CoV-1 and SARS-CoV-2 fusion peptides (FPs) are highly conserved, the cryo-electron microscopy structures of the SARS-CoV-1 and SARS-CoV-2 spike proteins show that the helix length of SARS-CoV-1 FP is longer than that of SARS-CoV-2 FP. In this work, we simulated the membrane-binding models of SARS-CoV-1 and SARS-CoV-2 FPs and compared the binding modes of the FPs with the POPC/POPE/cholesterol bilayer membrane. Our simulation results show that the SARS-CoV-2 FP binds to the bilayer membrane more effectively than the SARS-CoV-1 FP. It is seen that the short N-terminal helix of SARS-CoV-2 FP is more favorable to insert into the target membrane than the long N-terminal helix of SARS-CoV-1 FP. Meanwhile, the potential of mean force calculations showed that the SARS-CoV-2 FP would prefer only one binding mode (N-terminal binding), whereas the SARS-CoV-1 FP has two favorable membrane-binding modes (C-terminal and N-terminal binding modes). Moreover, in the case of SARS-CoV-1 FP binding to the target membrane, the transition between the two binding modes is relatively fast. Finally, we discovered that the membrane-binding mode would influence the helix length of SARS-CoV-1 FP, while the helix length of SARS-CoV-2 FP could be stably maintained in the membrane-bound configurations. This work suggests that the short helix might endow the FP with high membrane-anchoring strength. In particular, the membrane-penetrating residues (Phe, Ile, and Leu) of short α-helix interact with the cell membrane more strongly than those of long α-helix.

Effect of Disulfide Bridge on the Binding of SARS-CoV-2 Fusion Peptide to Cell Membrane: A Coarse-Grained Study

“…In addition, our CAVS simulations show that the stable helical structure enables the hydrophobic residues to interact strongly with cholesterol, which endows the FP-L with a higher membrane-binding strength than the FP-S. This observation is consistent with the previous all-atom MD simulation results. , Finally, we investigated the effect of the disulfide bond between Cys840 and Cys851 on the membrane binding of the FP-L, finding that the disulfide bridge stabilizes the helical structure, which should strengthen the binding between the FP-L and the bilayer membrane.…”

“…This observation is consistent with the previous all-atom MD simulation results. 31 , 64 Finally, we investigated the effect of the disulfide bond between Cys840 and Cys851 on the membrane binding of the FP-L, finding that the disulfide bridge stabilizes the helical structure, which should strengthen the binding between the FP-L and the bilayer membrane.…”

Role of cholesterol-recognition motifs in the infectivity of SARS-CoV-2 variants

“…Although the amino acid sequences of both FPs are quite similar ( Fig. 2 C), the corresponding cryo-electron microscopy structures show that the helix length of SARS-CoV FP is longer than that of the SARS-CoV-2 FP [36] . The higher hydrophobicity of the SARS-CoV-2 FP may also contribute to disrupting the target cell membrane [37] .…”

“…Importantly, the increase in membrane flexibility is more pronounced in the more rigid, Lo plasma membrane regions rich in cholesterol [35] . Shen et al [36] have recently compared the binding modes of SARS-CoV and SARS-CoV-2 FPs using in silico molecular dynamics. They showed that SARS-CoV-2 FP binds to a synthetic POPC/POPE/cholesterol bilayer membrane more effectively than the SARS-CoV FP [36] .…”

“…Shen et al [36] have recently compared the binding modes of SARS-CoV and SARS-CoV-2 FPs using in silico molecular dynamics. They showed that SARS-CoV-2 FP binds to a synthetic POPC/POPE/cholesterol bilayer membrane more effectively than the SARS-CoV FP [36] . Although the amino acid sequences of both FPs are quite similar ( Fig.…”