Hydrated Phospholipid Bilayers Research Articles

Atomistic Molecular Dynamics Simulations of Propofol and Fentanyl in Phosphatidylcholine Lipid Bilayers.

Atomistic molecular dynamics (MD) and steered MD simulations in combination with umbrella sampling methodology were utilized to study the general anesthetic propofol and the opioid analgesic fentanyl and their interaction with lipid bilayers, which is not yet fully understood. These molecules were inserted into two different fully hydrated phospholipid bilayers, namely, dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC), to investigate the effects that these drugs have on the bilayer. We determined the role of the lipid chain length and saturation on the behavior of the two drugs. Pure, fully hydrated DOPC and DPPC bilayers were also simulated, and the results were in excellent agreement with the experimental values. Various structural and mechanical properties of each system, such as the area per lipid, area compressibility modulus, order parameter, lateral lipid diffusion, hydrogen bonds, and radial distribution functions, have been calculated to assess how the drug molecules affect the different bilayers. From the calculated results, we show that fentanyl and propofol generally follow similar trends in each bilayer but adopt different favorable positions close to the headgroup/chain interface at the carbonyl groups. Propofol was shown to selectively form hydrogen bonds at the carbonyl carbon in each bilayer, whereas fentanyl interacts with water molecules at the headgroup interface. From the calculated free-energy profiles, we determined that both molecules show a preference for the low-density, low-order acyl chain region of the bilayers and both significantly preferred the DOPC bilayer with propofol and fentanyl having energy minima at −6.66 and −43.07 kcal mol–1, respectively. This study suggests that different chain lengths and levels of saturation directly affect the properties of these two important molecules, which are seen to work together to control anesthesia in surgical applications.

Voltage-Dependent Profile Structures of a Kv-Channel via Time-Resolved Neutron Interferometry

Available experimental techniques cannot determine high-resolution three-dimensional structures of membrane proteins under a transmembrane voltage. Hence, the mechanism by which voltage-gated cation channels couple conformational changes within the four voltage sensor domains, in response to either depolarizing or polarizing transmembrane voltages, to opening or closing of the pore domain's ion channel remains unresolved. Single-membrane specimens, composed of a phospholipid bilayer containing a vectorially oriented voltage-gated K+ channel protein at high in-plane density tethered to the surface of an inorganic multilayer substrate, were developed to allow the application of transmembrane voltages in an electrochemical cell. Time-resolved neutron reflectivity experiments, enhanced by interferometry enabled by the multilayer substrate, were employed to provide directly the low-resolution profile structures of the membrane containing the vectorially oriented voltage-gated K+ channel for the activated, open and deactivated, closed states of the channel under depolarizing and hyperpolarizing transmembrane voltages applied cyclically. The profile structures of these single membranes were dominated by the voltage-gated K+ channel protein because of the high in-plane density. Importantly, the use of neutrons allowed the determination of the voltage-dependent changes in both the profile structure of the membrane and the distribution of water within the profile structure. These two key experimental results were then compared to those predicted by three computational modeling approaches for the activated, open and deactivated, closed states of three different voltage-gated K+ channels in hydrated phospholipid bilayer membrane environments. Of the three modeling approaches investigated, only one state-of-the-art molecular dynamics simulation that directly predicted the response of a voltage-gated K+ channel within a phospholipid bilayer membrane to applied transmembrane voltages by utilizing very long trajectories was found to be in agreement with the two key experimental results provided by the time-resolved neutron interferometry experiments.

Time-Resolved Neutron Interferometry and the Mechanism of Electromechanical Coupling in Voltage-Gated Ion Channels.

The mechanism of electromechanical coupling for voltage-gated ion channels (VGICs) involved in neurological signal transmission, primarily Nav- and Kv-channels, remains unresolved. Anesthetics have been shown to directly impact this mechanism, at least for Kv-channels. Molecular dynamics computer simulations can now predict the structures of VGICs embedded within a hydrated phospholipid bilayer membrane as a function of the applied transmembrane voltage, but significant assumptions are still necessary. Nevertheless, these simulations are providing new insights into the mechanism of electromechanical coupling at the atomic level in 3-D. We show that time-resolved neutron interferometry can be used to investigate directly the profile structure of a VGIC, vectorially oriented within a single hydrated phospholipid bilayer membrane at the solid-liquid interface, as a function of the applied transmembrane voltage in the absence of any assumptions or potentially perturbing modifications of the VGIC protein and/or the host membrane. The profile structure is a projection of the membrane's 3-D structure onto the membrane normal and, in the absence of site-directed deuterium labeling, is provided at substantially lower spatial resolution than the atomic level. Nevertheless, this novel approach can be used to directly test the validity of the predictions from molecular dynamics simulations. We describe the key elements of our novel experimental approach, including why each is necessary and important to providing the essential information required for this critical comparison of "simulation" vs "experiment." In principle, the approach could be extended to higher spatial resolution and to include the effects of anesthetics on the electromechanical coupling mechanism in VGICs.

Phospholipophilicity of CxHyN(+) amines: chromatographic descriptors and molecular simulations for understanding partitioning into membranes.

Using immobilized artificial membrane high-performance liquid chromatography (IAM-HPLC) the sorption affinity of 70 charged amine structures to phospholipids was determined. The amines contained only 1 charged moiety and no other polar groups, the rest of the molecule being aliphatic and/or aromatic hydrocarbon groups. We systematically evaluated the influence of the amine type (1°, 2°, 3° amines and quaternary ammonium), alkyl chain branching, phenyl ring positioning, charge positioning (terminal vs. central in the molecule) on the phospholipid-water partitioning coefficient (KPLIPW). These experimental results were compared with quantum-chemistry based three-dimensional (3D) molecular simulations of the partitioning of charged amines, including the most likely solute conformers, using a hydrated phospholipid bilayer in the COSMOmic module of COSMOtherm software. Both IAM-HPLC retention data and the simulations suggest that the molecular orientation of charged amines at the location in the bilayer with the lowest calculated Gibbs free energy exerts a strong influence over the partitioning within the membrane. The most favourable position of charged amines coincides with the region where the phosphate anions in the phospholipid bilayer are most abundant. Hydrocarbon units oriented in this layer are located more towards the aqueous phase and contribute less to the overall membrane affinity than hydrocarbon units extending into the more hydrophobic core of the bilayer. COSMOmic simulations explain most of the trends between the structural differences observed in IAM-HPLC based KPLIPW. For this set of cationic structures, the mean absolute difference between COSMOmic simulations and IAM-HPLC data, accounting only for amine type corrective increments, is 0.31 log units.

Role of hydration in phosphatidylcholine reverse micelle structure and gelation in cyclohexane: a molecular dynamics study.

In this work, we employ all-atom molecular dynamics simulations to examine the hydration response of phospholipid reverse micelles in cyclohexane. This ternary phospholipid-water-cyclohexane system is an important organogel forming system and the focus of this study is on gaining insight on the factors governing the gelation transition. We map the contributions rising from specific lipid-lipid and lipid-water interactions, and their response to increasing aggregate size and changes in water-to-lipid ratio. We find that, opposed to phospholipid-heptane organogels, in cyclohexane, lipid bridging and hydrogen bond driven stabilization of the lipid head group packing is at minor role in dictating the reverse micelle structural transitions corresponding to the organosol-organogel phase transition in this system. Instead, increasing the lipid head hydration changes the lipid packing factor directly which leads to gelation through the formation of long, wormlike micelles. Furthermore, the confined environment in the reverse micellar cores slows down the water dynamics significantly in comparison to fully hydrated phospholipid bilayers and at low water-to-lipid ratios this slow-down is even more significant. The findings map the role of hydration at microscopic level in these systems and could enable tailoring reverse micellar systems for applications relying on the structure and dynamics of the reverse micelles. Examples include such as drug transport, nanotemplating, or confined chemistry in the reverse micelle core water space, e.g., in catalysis.

Expression, purification, and micelle reconstitution of antimicrobial piscidin 1 and piscidin 3 for NMR studies

Piscidin 1 and piscidin 3, which were discovered in the mast cells of hybrid striped sea bass, are homologous antimicrobial peptides that are active against drug-resistant bacteria. Piscidin 1, the more antimicrobial and hemolytic peptide, also has anti-HIV-1 and anti-cancer properties. To understand the reasons underlying the different biological activities of the two peptides and identify principles to design antimicrobial drugs with improved efficacy and lower toxicity, their atomic-level structures must be obtained under physiologically-relevant conditions. High-resolution backbone structures of both piscidins exist in the presence of hydrated phospholipid bilayers but full structures that include the side chains are missing. Here, the piscidins 1 and 3 genes were cloned into the TrpLE vector. The corresponding TrpLE-piscidin fusion partners were expressed in Escherichia coli and recovered from inclusion bodies. Following steps that included Ni–NTA chromatography, cyanogen bromide cleavage of the fusion proteins, and reverse-phase HPLC, purified piscidins 1 and 3 were recovered in very good yield and characterized by NMR. High quality 15N-1H HSQC spectra of piscidins 1 and 3 bound to SDS micelles were collected, demonstrating the feasibility of producing and purifying the isotopically-labeled piscidin peptides required to determine their full structures by multidimensional NMR spectroscopy.

Molecular dynamics simulations of the interactions of DMSO, mono- and polyhydroxylated cryosolvents with a hydrated phospholipid bilayer

Molecular dynamics (MD) simulations have been used to investigate the interactions of a variety of hydroxylated cryosolvents (glycerol, propylene glycol and ethylene glycol), methanol and dimethyl sulfoxide (DMSO) in aqueous solution with a 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) bilayer in its fluid phase at 323K. Each cryosolvent induced lateral expansion of the membrane leading to thinning of the bilayer and resulting in disordering of the lipid hydrocarbon chains. Propylene glycol and DMSO were observed to exhibit a greater disordering effect on the structure of the membrane than the other three alcohols. Closer examination exposed a number of effects on the lipid bilayer as a function of the molecular size and hydrogen bonding capacity of the cryosolvents. Analyses of hydrogen bonds revealed that increased concentrations of the polyhydroxylated cryosolvents induced the formation of a cross-linked cryosolvent layer across the surface of the membrane bilayer. This effect was most pronounced for glycerol at sufficiently high concentrations, which displayed a comparatively enhanced capacity to induce cross-linking of lipid headgroups resulting in the formation of extensive hydrogen bonding bridges and the promotion of a dense cryosolvent layer across the phospholipid bilayer.

Low-ε Static Probe Development for15N-1H Solid-state NMR Study of Membrane Proteins for an 800 MHz NB Magnet

H heteronuclear dipolar coupling in dilute membrane proteins oriented in hydrated anddielectrically lossy lipid environments. The system employed a 800 MHz narrow-bore magnet. A solenoid coilstrip shield was used to reduce deleterious RF sample heating by minimizing the conservative electric fieldsgenerated by the double-tuned resonator at high magnetic fields. The probe's design, construction, andperformance in solid-state NMR experiments at high magnetic fields are described here. Such high-resolutionsolid-state NMR spectroscopic analysis of static oriented samples in hydrated phospholipid bilayers or bicellescould aid the structural analysis of dilute biological membrane proteins.Key Words : Solid-state NMR probe, Low- e, Probe design, Membrane proteins, BicellesIntroductionMembrane proteins are important in various essentialsystems and regulatory processes, ranging from the com-plicated network of cellular communications to the meta-bolism and breaking down of unwanted substances in thehuman body. Hundreds of diseases involve the mis-foldingor mis-assembling of integral membrane proteins and over60% of all drug molecules target membrane proteins.Despite their importance, these protein's intrinsic structure-function relationships are not understood as their three-dimensional structures have not been fully elucidated. Thestudy of membrane proteins by current methods is hamperedby the need of a native bilayer environment, which is diffi-cult using most biophysical techniques. They are notoriouslydifficult to crystallize for X-ray crystallography and theirslow reorientation rates when combined with lipids or deter-gents hinder the use of conventional solution NMR (NuclearMagnetic Resonance) techniques. Solid-state NMR spectroscopy is a relatively new meansof investigating the structures of solid biological samples.

Twelve transmembrane helices form the functional core of mammalian MATE1

MATE1 and MATE2/2‐K, the mammalian organic cation/H+ (OC/H+) exchangers, are key players in renal and hepatic secretion of cationic drugs. They belong to a superfamily of transport proteins (Multidrug And Toxin Extruders) with 1000+ members. The x‐ray structure of the prototypic MATE family member, NorM from Vibrio cholera, shows a protein fold comprised of 12 transmembrane helices (TMHs), as predicted by hydropathy analysis of the majority of MATE transporters. However, the mammalian MATEs are predicted to have a C‐terminal 13th TMH. Here we confirmed the presence of the 13th TMH in mammalian MATE1. Whereas the C‐termini of epitope‐tagged, full length human, rabbit and mouse MATE1 were accessible to antibodies from the extracellular face of the membrane, truncation of these proteins at or near the junction between the 13th TMH and the long cytoplasmic loop that precedes it resulted in proteins that (i) trafficked to the membrane, (ii) had a cytoplasmic C‐terminus, and (iii) supported substrate transport. The latter observation indicates that the functional ‘core structure’ of mammalian MATE consists of the first 12 TMHs, whereas the 13th TMH is not necessary for essential function. Therefore, we used the x‐ray structure of NorM to develop a homology model of the 3D structure of hMATE1 that proved to be stable in Molecular Dynamic simulations when placed (in silico) in a hydrated phospholipid bilayer.

The Open Conformation of the Mg2+ Channel CorA from Solvent Accessibility and Distance Constraints

Using a combination of electrophysiology and spectroscopic approaches we have recently shown that CorA acts as a Mg2+-gated Mg2+-selective channel. NiEddA/O2 accessibility together with intersubunit distances were measured in two conditions: 1) Saturating Mg2+, which stabilizes CorA in the closed conformation and 2) The nominal absence of divalent ions, which stabilizes the open state. Here, we use a computational approach for incorporating both solvent accessibility data and distance constraints through restrained molecular dynamics (MD) simulations using CorA in a closed conformation as the starting structure. The accessibility restraints were enforced through interactions between a pseudoatom representation of the spin-label and environmental probe-surrounding particles. Intersubunit Cβ-Cβ distances estimated from DEER experiments, together with the accessibility data were used to generate hundreds of models by varying the upper and lower bound of distance constraints and increasing the number of MD refining cycles. The top 25 models show structural convergence especially around the stalk and inner helices, where the EPR restraints were imposed. After a second round of refinement, the stability of the top ranked structure was evaluated by an all-atom MD simulation in a fully hydrated phospholipid bilayer. After 2ns of the simulation, the RMSD of the stalk and inner helices is stable around 4-5A. Based on the pore-radius profile, the permeation pathway has dilated enough to allow a hydrated Mg2+, as expected if this conformation is conductive. A linear interpolation between the closed and open conformations suggests a gating mechanism for CorA, where the tips of the stalk helix come together like the ribs of an umbrella. After a kink, this motion translates into an expansion of the cavity and the mouth of the pore opens up with a motion reminiscent of an iris of a camera.

Head-to-Tail Interaction between Amphotericin B and Ergosterol Occurs in Hydrated Phospholipid Membrane

Amphotericin B (AmB) is thought to exert its antifungal activity by forming an ion-channel assembly in the presence of ergosterol. In the present study we aimed to elucidate the mode of molecular interactions between AmB and ergosterol in hydrated phospholipid bilayers using the rotational echo double resonance (REDOR) spectra. We first performed (13)C{(19)F}REDOR experiments with C14-(19)F-labeled AmB and biosynthetically (13)C-labeled ergosterol and implied that both "head-to-head" and "head-to-tail" orientations occur for AmB-ergosterol interaction in the bilayers. To further confirm the "head-to-tail" pairing, (13)C-labeled ergosterol at the dimethyl terminus (C26/C27) was synthesized and subjected to the REDOR measurements. The spectra unambiguously demonstrated the presence of a "head-to-tail" orientation for AmB-ergosterol pairing. In order to obtain information on the position of the dimethyl terminus of ergosterol in membrane, (13)C{(31)P}REDOR were carried out using the labeled ergosterol and the phosphorus atom of a POPC headgroup. Significant REDOR dephasing was observed at the C26/C27 signal of ergosterol in the presence of AmB, but not in the absence of AmB, clearly indicating that the side-chain terminus of ergosterol in the AmB complex comes close to the bilayer surface.

Statistical Convergence of Equilibrium Properties in Simulations of Molecular Solutes Embedded in Lipid Bilayers.

In recent years, atomistic molecular simulations have become a method of choice for studying the interaction of small molecules, peptides, and proteins with biological membranes. Here, we critically examine the statistical convergence of equilibrium properties in molecular simulations of two amino acid side-chain analogs, leucine and arginine, in the presence of a hydrated phospholipid bilayer. To this end, the convergence of the standard binding free energy for the reversible insertion of the solutes in the bilayer is systematically assessed by evaluating dozens of separate sets of umbrella sampling calculations for a total simulation time exceeding 400 μs. We identify rare and abrupt transitions in bilayer structure as a function of solute insertion depth. These transitions correspond to the slow reorganization of ionic interactions involving zwitterionic phospholipid headgroups when the solutes penetrate the lipid-water interface and when arginine is forced through the bilayer center. These rare events are shown to constitute hidden sampling barriers that limit the rate of convergence of equilibrium properties and result in systematic sampling errors. Our analysis demonstrates that the difficulty of attaining convergence for lipid bilayer-embedded solutes has, in general, been drastically underestimated. This information will assist future studies in improving accuracy by selecting a more appropriate reaction coordinate or by focusing computational resources on those regions of the reaction coordinate that exhibit slow convergence of equilibrium properties.

Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes.

Triclocarban and triclosan, two potent antibacterial molecules present in many consumer products, have been subject to growing debate on a number of issues, particularly in relation to their possible role in causing microbial resistance. In this computational study, we present molecular-level insights into the interaction between these antimicrobial agents and hydrated phospholipid bilayers (taken as a simple model for the cell membrane). Simulations are conducted by a novel 'dual-resolution' molecular dynamics approach which combines accuracy with efficiency: the antimicrobials, modelled atomistically, are mixed with simplified (coarse-grain) models of lipids and water. A first set of calculations is run to study the antimicrobials' transfer free energies and orientations as a function of depth inside the membrane. Both molecules are predicted to preferentially accumulate in the lipid headgroup-glycerol region; this finding, which reproduces corresponding experimental data, is also discussed in terms of a general relation between solute partitioning and the intramembrane distribution of pressure. A second set of runs involves membranes incorporated with different molar concentrations of antimicrobial molecules (up to one antimicrobial per two lipids). We study the effects induced on fundamental membrane properties, such as the electron density, lateral pressure and electrical potential profiles. In particular, the analysis of the spontaneous curvature indicates that increasing antimicrobial concentrations promote a 'destabilizing' tendency towards non-bilayer phases, as observed experimentally. The antimicrobials' influence on the self-assembly process is also investigated. The significance of our results in the context of current theories of antimicrobial action is discussed.

Numerical studies of the membrane fluorescent dyes dynamics in ground and excited states

Fluorescence methods are widely used in studies of biological and model membranes. The dynamics of membrane fluorescent markers in their ground and excited electronic states and correlations with their molecular surrounding within the fully hydrated phospholipid bilayer are still not well understood. In the present work, Quantum Mechanical (QM) calculations and Molecular Dynamics (MD) simulations are used to characterize location and interactions of two membrane polarity probes (Prodan; 6-propionyl-2-dimethylaminonaphthalene and its derivative Laurdan; 2-dimethylamino-6-lauroylnaphthalene) with the dioleoylphosphatidylcholine (DOPC) lipid bilayer model. MD simulations with fluorophores in ground and excited states are found to be a useful tool to analyze the fluorescent dye dynamics and their immediate vicinity. The results of QM calculations and MD simulations are in excellent agreement with available experimental data. The calculation shows that the two amphiphilic dyes initially placed in bulk water diffuse within 10 ns towards their final location in the lipid bilayer. Analysis of solvent relaxation process in the aqueous phase occurs on the picoseconds timescale whereas it takes nanoseconds at the lipid/water interface. Four different relaxation time constants, corresponding to different relaxation processes, where observed when the dyes were embedded into the membrane.

Efficient heteronuclear dipolar decoupling in NMR of static solid samples using phase-wiggled two-pulse phase modulation

A new scheme using phase-wiggled two-pulse phase modulation (PW-TPPM) is proposed for efficient heteronuclear dipolar decoupling in nuclear magnetic resonance (NMR) of static solid samples. The two pulses within each TPPM element have different alternating phase angles so that these elements become phase-wiggled. It is derived theoretically that such phase wiggling causes a resonance for additional averaging of the residual heteronuclear dipolar interactions and thus significantly improves decoupling efficiency in stationary solids. A static 15N-acetyl-valine crystal sample and a 15N-labeled helical peptide sample aligned in hydrated phospholipid bilayers were used to illustrate the advantages of this new scheme.

Physical study of dynamics in fully hydrated phospholipid bilayers

We studied the thermotropic phase behavior of a phospholipid membrane bilayer of dimyristoylphosphatidylcholine (DMPC) under excess water conditions. We also investigated the effect induced by the antimicrobial peptide, gramicidin D (GrD), when inserted into the membrane bilayer. Several techniques were used to collect information on different properties and various spatial and temporal regimes, including differential scanning calorimetry, fixed energy window neutron scattering, pulsed-field gradient nuclear magnetic resonance and molecular dynamics simulations. We obtained data on the main phase transition (gel–liquid crystalline) temperature of the bilayer system and on the long-range diffusion coefficient for both phospholipids and hydration water. Moreover, we demonstrated the effect of transition on microscopic molecular mobility, perpendicular and parallel to the membrane plane. The influence of gramicidin on these properties is also discussed.

The role of proline residues in the structure and function of human MT2 melatonin receptor

Melatonin functions as an essential regulator of various physiological processes in all vertebrate species. In mammals, two G protein-coupled melatonin receptors (GPCR) mediate some melatonin's actions: MT1 and MT2. Transmembrane domains (TM) of most GPCRs contain a set of highly conserved proline residues that presumably play important structural and functional roles. As TM segments of MT2 receptor display several interesting differences in expression of specific proline residues compared to other rhodopsin-like receptors (rGPCRs), we investigated the role of proline residues in the structure and function of this receptor. All prolines in TM segments of MT2 receptor were individually replaced with alanine and/or glycine. In addition, the unusual NAxxY motif located in TM7 was mutated to generate highly conserved NPxxY motif found in the majority of rGPCR proteins. Following transient expression in CHO-K1 cells, binding properties of the mutant receptors and their ability to transduce signals were analyzed using (125)I-mel- and [(35)S]GTPgammaS-binding assays, respectively. The impact of the performed mutations on the receptor structure was assessed by molecular dynamic simulations of MT2 receptors embedded in the fully hydrated phospholipid bilayer. Our results indicate that residues P174, P212 and P266 are important for the ligand binding and/or signaling of the human MT2 receptor. We also show that changes within the unusual NAxxY sequence in the TM7 (mutations A305P and A305V) produce defective MT2 receptors indicating an important role of this motif in the function of melatonin receptors.

Effect of Trehalose on a Phospholipid Membrane under Mechanical Stress

Explicit solvent molecular dynamics simulations were used to investigate at atomic resolution the effect of trehalose on a hydrated phospholipid bilayer under mechanical stress (stretching forces imposed in the form of negative lateral pressure). Simulations were performed in the absence or presence of trehalose at 325K, and with different values for negative lateral pressure. In the concentration regime (2 molal) and range of lateral pressures (1 to −250 bar) investigated, trehalose was found to interact directly with the membrane, partially replacing water molecules in the formation of hydrogen bonds with the lipid headgroups. Similar to previous findings in the context of thermal stress, the number, degree of bridging, and reaching depth of these hydrogen bonds increased with the magnitude of perturbation. However, at the concentration considered, trehalose was not sufficient to preserve the integrity of the membrane structure and to prevent its extreme elongation (and possible disruption) under the effect of stretching forces.

The influence of polyhydroxylated compounds on a hydrated phospholipid bilayer: a molecular dynamics study

Molecular dynamics simulations are used to investigate the interaction of the polyhydroxylated cosolutes (CSLs) methanol (MET), ethylene glycol (ETG), glycerol (GLY), glucose (GLU) and trehalose (TRH) with a hydrated phospholipid bilayer in the liquid–crystalline phase at 325 K. The comparison is performed at constant effective concentration of CSL hydroxyl groups. The results (along with available experimental data) lead to the formulation of two distinct mechanisms for the interaction of polyhydroxylated compounds with lipid bilayers. The alcohol-like mechanism (active for MET and ETG) involves preferential affinity of the CSL (compared to water) for the superficial region of the bilayer interior, and is driven by the hydrophobic effect. It results in a lateral expansion of the membrane, a disorder increase within the bilayer, and a partial substitution of water by CSL molecules at the hydrogen-bonding sites provided by the membrane (predominantly at the level of the ester groups). The sugar-like mechanism (active for GLU and TRH) involves preferential affinity of the CSL (compared to water) for the bilayer surface (formation of a coating layer), and is driven by entropic effects. It results in the absence of lateral expansion and change in disorder within the bilayer, and in a partial substitution of water by CSL molecules (predominantly at the level of the phosphate groups). It also involves the bridging of lipid molecules via hydrogen-bonded CSL molecules, a phenomenon that may have implications in the context of membrane stabilisation by sugars. Hydrogen bonding itself is not viewed as a driving force for these two mechanisms, which only involve the (partial) substitution of water–lipid by CSL–lipid hydrogen bonds (the sum of the two remaining essentially constant, irrespective of the nature and concentration of the CSL).

A Quantitative Coarse-Grain Model for Lipid Bilayers

A simplified particle-based computer model for hydrated phospholipid bilayers has been developed and applied to quantitatively predict the major physical features of fluid-phase biomembranes. Compared with available coarse-grain methods, three novel aspects are introduced. First, the main electrostatic features of the system are incorporated explicitly via charges and dipoles. Second, water is accurately (yet efficiently) described, on an individual level, by the soft sticky dipole model. Third, hydrocarbon tails are modeled using the anisotropic Gay-Berne potential. Simulations are conducted by rigid-body molecular dynamics. Our technique proves 2 orders of magnitude less demanding of computational resources than traditional atomic-level methodology. Self-assembled bilayers quantitatively reproduce experimental observables such as electron density, compressibility moduli, dipole potential, lipid diffusion, and water permeability. The lateral pressure profile has been calculated, along with the elastic curvature constants of the Helfrich expression for the membrane bending energy; results are consistent with experimental estimates and atomic-level simulation data. Several of the results presented have been obtained for the first time using a coarse-grain method. Our model is also directly compatible with atomic-level force fields, allowing mixed systems to be simulated in a multiscale fashion.