The critical role of aromatic residues in the binding of the SARS-CoV-2 fusion peptide to phospholipid bilayer membranes.

The critical role of aromatic residues in the binding of the SARS-CoV-2 fusion peptide to phospholipid bilayer membranes.

Publication date: Oct 10, 2024

Based on the SARS-CoV-2 fusion peptide (FP) structure determined from the NMR experiment, we created six FP models under different environmental conditions to explore the effects of salt and cholesterol on FP-membrane binding. The all-atom molecular dynamics (MD) simulation results indicated that ionic environments notably impact the FP structure as well as the stability of the helical elements within the peptide. Our findings highlighted the unpredictable influence of ions on the secondary structures and dynamics of the FP, emphasizing the complexity and sensitivity of the peptide’s conformations to ionic conditions. When exploring the peptide’s interaction with a cholesterol-free phospholipid bilayer membrane, we found that the helical elements of the FP remain stable irrespective of the salt type (Na or Ca). This result emphasizes the crucial role of phospholipid bilayer membranes in supporting the secondary structures of the FP. The MD simulation results showed that Ca ions facilitated deeper membrane penetration than Na ions, highlighting the critical role of calcium ions in the FP-membrane binding. Our study indicates the essential role of the aromatic residues (such as Phe833 and Tyr837) in the FP-membrane binding process. Finally, we investigated the FP-membrane binding patterns in the presence of cholesterol. The MD simulation results demonstrated that the coupling of Ca ions and cholesterol would also benefit the FP-membrane binding. Furthermore, our findings reveal that while the type of ion and cholesterol content exert varied and unpredictable influences on FP-membrane binding patterns, aromatic residues like tyrosine (Tyr) and phenylalanine (Phe) play an essential role in FP-membrane binding. In particular, deep mutational scanning (DMS) experiments have confirmed that mutating phenylalanine in the FP significantly decreases viral mutational fitness, emphasizing the pivotal role of phenylalanine residues in membrane fusion. This knowledge can aid in developing more effective therapeutic strategies targeting the viral fusion peptide and its key amino acids, ultimately contributing to developing treatments and vaccines against the virus.

Concepts Keywords
Calcium Aromatic
Cholesterol Bilayer
Environmental Binding
Molecular Cholesterol
Viral Critical
Fp
Fusion
Ions
Membrane
Peptide
Phenylalanine
Phospholipid
Residues
Sars
Simulation

Semantics

Type Source Name
disease IDO role
drug DRUGBANK Cholesterol
drug DRUGBANK Calcium cation
disease IDO process
drug DRUGBANK L-Tyrosine
drug DRUGBANK L-Phenylalanine
drug DRUGBANK Succimer
drug DRUGBANK Amino acids

Original Article

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