Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation.

Preferential lipid solvation of the G-protein-coupled A2A adenosine receptor (A2AR) is evaluated from 35 µs of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining estimates of the free energy of solvation by different lipids for the receptor in different activation states. Results indicate preference for solvation by unsaturated chains, which favors the active receptor. A model for lipid-dependent G-protein-coupled receptor activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The entropies associated with moving saturated and unsaturated lipids from bulk to A2AR's first solvation shell are evaluated. Overall, the acyl chains are more disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, and this effect is augmented for the saturated chains, which are relatively more ordered in bulk.

How Do Ethanolamine Plasmalogens Contribute to Order and Structure of Neurological Membranes?

Ethanolamine plasmalogen (EtnPLA) is a conical-shaped ether lipid and an essential component of neurological membranes. Low stability against oxidation limits its study in experiments. The concentration of EtnPLA in the bilayer varies depending on cell type and disease progression. Here we report on mixed bilayers of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphoethanolamine (C18(Plasm)-18:1PE, PLAPE), an EtnPLA lipid subtype, at mole ratios of 2:1, 1:1, and 1:2. We present X-ray diffuse scattering (XDS) form factors F(qz) from oriented stacks of bilayers, related electron-density profiles, and hydrocarbon chain NMR order parameters. To aid future research on EtnPLA lipids and associated proteins, we have also extended the CHARMM36 all-atom force field to include the PLAPE lipid. The ability of the new force-field parameters to reproduce both X-ray and NMR structural properties of the mixed bilayer is remarkable. Our results indicate a thickening of the bilayer upon incorporation of increasing amounts of PLAPE into mixed bilayers, a reduction of lateral area per molecule, and an increase in lipid tail-ordering. The lateral compressibility modulus (KA) calculated from simulations yielded values for PLAPE similar to POPC.

Developing and Testing of Lipid Force Fields with Applications to Modeling Cellular Membranes.

The amphipathic nature of the lipid molecule (hydrophilic head and hydrophobic tails) enables it to act as a barrier between fluids with various properties and to sustain an environment where the processes critical to life may proceed. While computer simulations of biomolecules primarily investigate protein conformation and binding to drug-like molecules, these interactions often occur in the context of a lipid membrane. Chemical specificity of lipid models is essential to accurately represent the complex environment of the lipid membrane. This review discusses the development and performance of currently used chemically specific lipid force fields (FF) such as the CHARMM, AMBER, GROMOS, OPLS, and MARTINI families. Considerations in lipid FF development including lipid diversity, temperature dependence, phase behavior, and effects of atomic polarizability are considered, as well as methods and goals of parametrization. Applications of these FFs to complex and diverse models for cellular membranes are summarized. Lastly, areas for future development, such as efficient inclusion of long-range Lennard-Jones interactions (significant in transitions from polar to apolar media), accurate transmembrane dipole potential, and diffusion under periodic boundary conditions are considered.

Isothermal Titration Calorimetry of Be2+ with Phosphatidylserine Models Guides All-Atom Force-Field Development for Lipid-Ion Interactions.

Beryllium has multiple industrial applications but exposure to its dust during manufacturing is associated with developing chronic inflammation in lungs known as berylliosis. Besides binding to specific alleles of MHC-II, Be2+ was recently found to compete with Ca2+ for binding sites on phosphatidylserine-containing membranes and inhibit recognition of this lipid by phagocytes. Computational studies of possible molecular targets for this small toxic dication are impeded by the absence of a reliable force field. This study introduces parameters for Be2+ for the CHARMM36 additive force field that represent interactions with water, including free energy of hydration and ion-monohydrate interaction energy and separation distance; and interaction parameters describing Be2+ affinity for divalent ion binding sites on lipids, namely phosphoryl and carboxylate oxygens. Results from isothermal titration calorimetry experiments for the binding affinities of Be2+ to dimethyl phosphate and acetate ions reveal that Be2+ strongly binds to phosphoryl groups. Revised interaction parameters for Be2+ with these types of oxygens reproduce experimental affinities in solution simulations. Surface tensions calculated from simulations of DOPS monolayers with varied concentrations of Be2+ are compared with prior results from Langmuir monolayer experiments, verifying the compacting effect that produces greater surface tensions (lower pressures) for Be2+-bound monolayers at the same surface area in comparison with K+. The new parameters will enable simulations that should reveal the mechanism of Be2+ interference with molecular recognition and signaling processes.

Parameterization of the CHARMM All-Atom Force Field for Ether Lipids and Model Linear Ethers.

Linear ethers such as polyethylene glycol have extensive industrial and medical applications. Additionally, phospholipids containing an ether linkage between the glycerol backbone and hydrophobic tails are prevalent in human red blood cells and nerve tissue. This study uses ab initio results to revise the CHARMM additive (C36) partial-charge and dihedral parameters for linear ethers and develop parameters for the ether-linked phospholipid 1,2-di- O-hexadecyl- sn-glycero-3-phosphocholine (DHPC). The new force field, called C36e, more accurately represents the dihedral potential energy landscape and improves the densities and free energies of hydration of linear ethers. C36e allows more water to penetrate into a DHPC bilayer, increasing the surface area per lipid compared to simulations carried out with the original C36 ether parameters and improving the overall structural properties obtained from X-ray and neutron scattering. Comparison with an ester-linked DPPC bilayer (1,2-dipalmitoyl- sn-phosphatidylcholine) reveals that the ether linkage increases water organization in the headgroup region. This effect is a likely explanation for the experimentally lower water permeability of bilayers composed of ether-linked lipids.

Comparison of Additive and Polarizable Models with Explicit Treatment of Long-Range Lennard-Jones Interactions Using Alkane Simulations.

Long-range Lennard-Jones (LJ) interactions have a significant impact on the structural and thermodynamic properties of nonpolar systems. While several methods have been introduced for the treatment of long-range LJ interactions in molecular dynamics (MD) simulations, increased accuracy and extended applicability is required for anisotropic systems such as lipid bilayers. The recently refined Lennard-Jones particle-mesh Ewald (LJ-PME) method extends the particle-mesh Ewald (PME) method to long-range LJ interactions and is suitable for use with anisotropic systems. Implementation of LJ-PME with the CHARMM36 (C36) additive and CHARMM Drude polarizable force fields improves agreement with experiment for density, isothermal compressibility, surface tension, viscosity, translational diffusion, and 13C T1 relaxation times of pure alkanes. Trends in the temperature dependence of the density and isothermal compressibility of hexadecane are also improved. While the C36 additive force field with LJ-PME remains a useful model for liquid alkanes, the Drude polarizable force field with LJ-PME is more accurate for nearly all quantities considered. LJ-PME is also preferable to the isotropic long-range correction for hexadecane because the molecular order extends to nearly 20 Å, well beyond the usual 10-12 Å cutoffs used in most simulations.