The different interactions of lysine and arginine side chains with lipid membranes.

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 k...