Arginine in Membranes: The Connection Between Molecular Dynamics Simulations and Translocon-Mediated Insertion Experiments

Abstract

Several laboratories have carried out molecular dynamics (MD) simulations of arginine interactions with lipid bilayers and found that the energetic cost of placing arginine in lipid bilayers is an order of magnitude greater than observed in molecular biology experiments in which Arg-containing transmembrane helices are inserted across the endoplasmic reticulum membrane by the Sec61 translocon. We attempt here to reconcile the results of the two approaches. We first present MD simulations of guanidinium groups alone in lipid bilayers, and then, to mimic the molecular biology experiments, we present simulations of hydrophobic helices containing single Arg residues at different positions along the helix. We discuss the simulation results in the context of molecular biology results and show that the energetic discrepancy is reduced, but not eliminated, by considering free energy differences between Arg at the interface and at the center of the model helices. The reduction occurs because Arg snorkeling to the interface prevents Arg from residing in the bilayer center where the energetic cost of desolvation is highest. We then show that the problem with MD simulations is that they measure water-to-bilayer free energies, whereas the molecular biology experiments measure the energetics of partitioning from translocon to bilayer, which raises the fundamental question of the relationship between water-to-bilayer and water-to-translocon partitioning. We present two thermodynamic scenarios as a foundation for reconciliation of the simulation and molecular biology results. The simplest scenario is that translocon-to-bilayer partitioning is independent of water-to-bilayer partitioning; there is no thermodynamic cycle connecting the two paths.

Apolar surface area determines the efficiency of translocon-mediated membrane-protein integration into the endoplasmic reticulum

“…Likewise, the ER membrane, which, like all biological membranes, has a high protein content, may offer an environment that is less apolar than a pure lipid bilayer (24). Indeed, the solvation parameters for partitioning of aliphatic and nonpolar aromatic side chains obtained here [approximately 10 and 7 cal∕ðmol · Å 2 Þ] are a factor 2.5 smaller than found in classical solute transfer experiments (13,(25)(26)(27)(28), suggesting that simple water-to-lipid partitioning measurements do not capture the full complexity of translocon-to-membrane partitioning (7). The asymmetry in the ΔG app curves, Figs.…”

“…Although the partitioning of transmembrane helices between the Sec61 translocon and the lipid membrane bears strong similarities to partitioning of solutes between water and lipid membranes, translocon-to-bilayer partitioning may not be equivalent to water-to-bilayer partitioning (7). Insights into the differences between the two partitioning processes might be revealed if the physicochemical properties of the translocon could be probed chemically.…”

Buried lysine, but not arginine, titrates and alters transmembrane helix tilt

“…Although some molecular dynamics simulations (10,11) have estimated larger energy barriers than translocon-mediated (12) or water-to-bilayer membrane protein-folding experiments (13) for moving Arg into the bilayer, careful consideration of experimental conditions and the underlying molecular context is leading to a convergence of findings from different methods (14)(15)(16). In particular, Arg side-chain snorkeling, helix off-center translocation, and membrane deformation all can contribute to maintaining (partial) hydration and thereby lowering the free energy for accommodating a charged residue within a lipid bilayer (14)(15)(16)(17)(18). Additionally, for cases in which the aqueous access to Arg may be impeded, structural manipulations to remove the obstruction can restore the accommodation of Arg within a bilayer (19).…”

Effects of L-amino Acids on Human Peripheral Neutrophil Granulocyte Activation

“…Other than being components of proteins, some amino acids have individual biological or biochemical effects. Leucine [2], arginine [3], glutamine [4], and glutamate [5] have been extensively studied as signaling agents. In addition to its important role as a neurotransmitter, glutamate signaling has been described in peripherial tissues, e.g.…”