Membrane Composition Reshapes the Folding Landscape of a pH-Responsive Peptide

Area of Science:

• Biophysics
• Membrane Biology
• Protein Folding

Background:

• Lipid composition is crucial for membrane protein behavior.
• The influence of membrane mechanics on protein free energy landscapes is not fully understood.

Purpose of the Study:

• To investigate how lipid composition affects the folding landscape of the pH low insertion peptide (pHLIP).
• To explore the dynamic interplay between peptide insertion and membrane structure.

Main Methods:

• Utilized surface-enhanced and ultrafast two-dimensional infrared spectroscopies.
• Studied the pH low insertion peptide (pHLIP) in membranes with varying lipid compositions.

Main Results:

• Anionic phosphatidylserine lipids facilitate more rigid insertion and direct alpha-helical folding of pHLIP at higher pH.
• Neutral membranes result in pathways with distinct intermediates and prolonged surface-bound states.
• Peptide insertion was observed to actively remodel the membrane, disrupting lipid packing and increasing water penetration.

Conclusions:

• The lipid bilayer acts as a dynamic energy landscape that guides and adapts to protein folding.
• This research provides a framework for understanding how membranes modulate cotranslational folding and prevent misfolding in vivo.