The Different Interactions of Lysine and Arginine Side Chains with Lipid Membranes

Abstract

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.

Transmembrane signaling in the sensor kinase DcuS of Escherichia coli : A long-range piston-type displacement of transmembrane helix 2

“…2 C and D). Positively charged Arg residues in a TM helix tend to move to a hydrophilic region to interact by H-bonds and electrostatically (16,17). To reach this environment, Arg residues must move vertically toward the nearest watermembrane interface with a corresponding shift of the TM helix.…”

Membrane Permeation of a Peptide: It Is Better to be Positive

“…8 . Allen et al 11 computed PMF of analogs of lysine and arginine and estimated that charged arginine can permeate through the membrane but not charged lysine. Recent experiments have confirmed those findings.…”

Self-association of a highly charged arginine-rich cell-penetrating peptide

“…The choice of the peptides is motivated by the biological interest in the high cellular uptake of arginine-rich peptides (RRPs), which has been the subject of several comparative studies (7)(8)(9)(10)(11). Oligo-arginine chains of 6-15 aa readily translocate across cell membranes (7,12), while the translocation efficiency of oligolysines of equal length is considerably lower (7,13).…”