Reversible Activation of pH-Responsive Cell-Penetrating Peptides in Model Cell Membrane Relies on the Nature of Lipid

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The pH response of pH-responsive cell-penetrating peptides in cell membrane is directly associated with many potential applications and cell activities such as drug delivery, membrane fusion, and protein folding, but it is still poorly understood. In this study, we used GALA as a model and applied sum frequency generation vibrational spectroscopy to systematically investigate the pH response of GALA in lipid bilayers with different hydrophobic length and lipid head groups. We determined the GALA structures in lipid bilayers by combining second-ordered amide I and amide III spectral signals, which can accurately differentiate the loop and α-helical structures at the interface. It is found that GALA can insert into fluid-phase lipid bilayers even at neutral pH, while lies down on the gel-phase lipid bilayer surface. Under acidic conditions, GALA inserts into both fluid-phase and gel-phase lipid bilayers. GALA adopts a mixed loop and α-helical structures in lipid bilayers. Besides, the reversible activation ...