Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations

Area of Science:

• Biophysics
• Computational Chemistry
• Molecular Biology

Background:

• Understanding peptide-membrane interactions is crucial for drug design and protein function.
• The folding and insertion mechanisms of designed peptides into lipid bilayers are not fully elucidated.

Purpose of the Study:

• To investigate the general mechanism of interfacial folding and membrane insertion for designed peptides.
• To explore the behavior of WALP and TMX peptide series using computational simulations.

Main Methods:

• Utilized an implicit membrane generalized Born model.
• Employed replica-exchange molecular dynamics simulations.
• Initiated simulations from extended peptide conformations in aqueous phase.

Main Results:

• Peptides localized at the membrane-solvent interface, forming helical secondary structures.
• Hydrophobic residues inserted into the membrane interior, driving insertion.
• WALP peptides and TMX-1 spontaneously inserted, forming transmembrane helices.
• TMX-3 exhibited a fluctuating membrane interface-bound form without insertion.

Conclusions:

• A general mechanism involving interfacial helical structure formation precedes membrane insertion for hydrophobic peptides.
• Implicit membrane models and advanced simulations can accurately predict peptide-membrane interactions.
• Findings guide experimental studies on membrane-associated peptide folding and insertion.