Ionic Strength and Solution Composition Dictate the Adsorption of Cell-Penetrating Peptides onto Phosphatidylcholine Membranes
2022
Nguyen, Man Thi Hong | Biriukov, Denys | Tempra, Carmelo | Baxova, Katarina | Martinez-Seara, Hector | Evci, Hüseyin | Singh, Vandana | Šachl, Radek | Hof, M. (Martin) | Jungwirth, Pavel | Javanainen, Matti | Vazdar, Mario
Adsorption of arginine-rich positively charged peptides onto neutral zwitterionic phosphocholine (PC) bilayers is a key step in the translocation of those potent cell-penetrating peptides into the cell interior. In the past, we have shown both theoretically and experimentally that polyarginines adsorb to the neutral PC-supported lipid bilayers in contrast to polylysines. However, comparing our results with previous studies showed that the results often do not match even at the qualitative level. The adsorption of arginine-rich peptides onto 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) may qualitatively depend on the actual experimental conditions where binding experiments have been performed. In this work, we systematically studied the adsorption of R₉ and K₉ peptides onto the POPC bilayer, aided by molecular dynamics (MD) simulations and fluorescence cross-correlation spectroscopy (FCCS) experiments. Using MD simulations, we tested a series of increasing peptide concentrations, in parallel with increasing Na⁺ and Ca²⁺ salt concentrations, showing that the apparent strength of adsorption of R₉ decreases upon the increase of peptide or salt concentration in the system. The key result from the simulations is that the salt concentrations used experimentally can alter the picture of peptide adsorption qualitatively. Using FCCS experiments with fluorescently labeled R₉ and K₉, we first demonstrated that the binding of R₉ to POPC is tighter by almost 2 orders of magnitude compared to that of K₉. Finally, upon the addition of an excess of either Na⁺ or Ca²⁺ ions with R₉, the total fluorescence correlation signal is lost, which implies the unbinding of R₉ from the PC bilayer, in agreement with our predictions from MD simulations.
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