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How arginine derivatives alter the stability of lipid membranes: dissecting the roles of side chains, backbone and termini.

ABSTRACT: Arginine (R)-rich peptides constitute the most relevant class of cell-penetrating peptides and other membrane-active peptides that can translocate across the cell membrane or generate defects in lipid bilayers such as water-filled pores. The mode of action of R-rich peptides remains a topic of controversy, mainly because a quantitative and energetic understanding of arginine effects on membrane stability is lacking. Here, we explore the ability of several oligo-arginines R[Formula: see text] and of an arginine side chain mimic R[Formula: see text] to induce pore formation in lipid bilayers employing MD simulations, free-energy calculations, breakthrough force spectroscopy and leakage assays. Our experiments reveal that R[Formula: see text] but not R[Formula: see text] reduces the line tension of a membrane with anionic lipids. While R[Formula: see text] peptides form a layer on top of a partly negatively charged lipid bilayer, R[Formula: see text] leads to its disintegration. Complementary, our simulations show R[Formula: see text] causes membrane thinning and area per lipid increase beside lowering the pore nucleation free energy. Model polyarginine R[Formula: see text] similarly promoted pore formation in simulations, but without overall bilayer destabilization. We conclude that while the guanidine moiety is intrinsically membrane-disruptive, poly-arginines favor pore formation in negatively charged membranes via a different mechanism. Pore formation by R-rich peptides seems to be counteracted by lipids with PC headgroups. We found that long R[Formula: see text] and R[Formula: see text] but not short R[Formula: see text] reduce the free energy of nucleating a pore. In short R[Formula: see text], the substantial effect of the charged termini prevent their membrane activity, rationalizing why only longer [Formula: see text] are membrane-active.

SUBMITTER: Verbeek SF

PROVIDER: S-EPMC8071801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The basic amino acids lysine (Lys) and arginine (Arg) play important roles in membrane protein activity, the sensing of membrane voltages, and the actions of antimicrobial, toxin, and cell-penetrating peptides. These roles are thought to stem from the strong interactions and disruptive influences of these amino acids on lipid membranes. In this study, we employ fully atomistic molecular dynamics simulations to observe, quantify, and compare the interactions of Lys and Arg with saturated phosphatidylcholine membranes of different thickness. We make use of both charged (methylammonium and methylguanidinium) and neutral (methylamine and methylguanidine) analogue molecules, as well as Lys and Arg side chains on transmembrane helix models. We find that the free energy barrier experienced by a charged Lys crossing the membrane is strikingly similar to that of a charged Arg (to within 2 kcal/mol), despite the two having different chemistries, H-bonding capability, and hydration free energies that differ by ?10 kcal/mol. In comparison, the barrier for neutral Arg is higher than that for neutral Lys by around 5 kcal/mol, being more selective than that for the charged species. This can be explained by the different transport mechanisms for charged or neutral amino acid side chains in the membrane, involving membrane deformations or simple dehydration, respectively. As a consequence, we demonstrate that Lys would be deprotonated in the membrane, whereas Arg would maintain its charge. Our simulations also reveal that Arg attracts more phosphate and water in the membrane, and can form extensive H-bonding with its five H-bond donors to stabilize Arg-phosphate clusters. This leads to enhanced interfacial binding and membrane perturbations, including the appearance of a trans-membrane pore in a thinner membrane. These results highlight the special role played by Arg as an amino acid to bind to, disrupt, and permeabilize lipid membranes, as well as to sense voltages for a range of peptide and protein activities in nature and in engineered bionanodevices.

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How arginine derivatives alter the stability of lipid membranes: dissecting the roles of side chains, backbone and termini.

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