The amphipatic pHD peptides (pH-dependent delivery peptides) have the unique property that they can form large, stable pores at acidic pH values, which makes them of direct interest to deliver cargo to specific cells and cell compartments. The 3D structures of these membrane-embedded pores are not amenable to experimental structural biology. To study the reaction coordinate of pHD membrane pore formation, we rely on experiment-guided atomic-level simulations and graph-based analyses of the peptides in aqueous solution, at the membrane interface, and embedded in the membrane. We find that, as anticipated from experiments, the peptides form small bundles when in aqueous solution. The membrane is largely perturbed by peptides at the interface. When stable peptide pores form in the membrane, lipids trapped inside sample highly unusual conformations and, together with hydrogen-bonded waters, help stabilize the pore. Research was supported in part by the National Institute of Health award no. 1R01GM151326-01 and by the computing time allocation PHDPORES from the JURECA-DC Supercomputing Cluster of the Forschungszentrum Jülich.
Bondar et al. (Sun,) studied this question.