Effect of Peptide Sequence Mutations on the Translocation of Charged Peptide Loops across Lipid Bilayers with Molecular Dynamics Simulations

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The hydrophobic core of the cell membrane is considered largely impermeable to charged molecules because of the large free energy barrier and corresponding long timescale (∼hours) for charge translocation. Contradicting this view, a variety of water-soluble peptides are known to translocate charged groups across the cell membrane on a surprisingly rapid ∼seconds timescale, for at least some peptides. In this work, we study the interconversion of single α-helix peptides with charged flanking loops between a surface-adsorbed and membrane-embedded state, which requires the translocation (or “flipping”) of charged loops across the bilayer.