Dipalmitoylphosphatidylcholine Bilayers Research Articles

An analysis of the dipalmitoylphosphatidylcholine bilayer gel phases predicted with molecular dynamics simulations using force fields from the GROMOS family

Dipalmitoylphosphatidylcholine is a phospholipid of major importance for biological systems. Molecular dynamics simulation investigations of this lipid focused on their behavior at human body temperature (≈ 37 °C or 310 K). For some applications, however, it is necessary to study its properties at room temperature (≈ 25 °C or 298 K). A small difference in temperature at this range is responsible for a phase transition in the lipid bilayer. Therefore, molecular dynamics simulations are carried out applying six different force fields from the GROMOS family to compare the less ordered phase (liquid-crystalline phase) with a more ordered phase (gel phase) of the hydrated bilayer of dipalmitoylphosphatidylcholine formed at 323 K and 298 K, respectively. The analysis of the bilayer structural quantities is used to evaluate order and packing at the two temperatures. The area per lipid and deuterium order parameter results are in agreement with simulation results from the literature and are also compared with experimental data. These parameters, however, do not provide a clear picture of the low-temperature gel phase present in the simulations using the force fields from the GROMOS family. To address this, a strategy for computing the lipid phase nematic order parameter is proposed, and a reference gel phase is simulated using the CHARMM36 force field for comparison. The results are consistent with other structural quantities but reveal a level of order that is below the expected for an ordered gel phase for the GROMOS force fields. Visual inspection of the simulation trajectories suggests the presence of a ripple phase. Overall, the GROMOS 54A8 provides the best performance among the tested GROMOS force fields for both investigated temperatures, even lacking a proper representation of the ordered gel phase.

Lipid bilayer properties potentially contributed to the evolutionary disappearance of betaine lipids in seed plants

BackgroundMany organisms rely on mineral nutrients taken directly from the soil or aquatic environment, and therefore, developed mechanisms to cope with the limitation of a given essential nutrient. For example, photosynthetic cells have well-defined responses to phosphate limitation, including the replacement of cellular membrane phospholipids with non-phosphorous lipids. Under phosphate starvation, phospholipids in extraplastidial membranes are replaced by betaine lipids in microalgae. In higher plants, the synthesis of betaine lipid is lost, driving plants to other strategies to cope with phosphate starvation where they replace their phospholipids by glycolipids.ResultsThe aim of this work was to evaluate to what extent betaine lipids and PC lipids share physicochemical properties and could substitute for each other. By neutron diffraction experiments and dynamic molecular simulation of two synthetic lipids, the dipalmitoylphosphatidylcholine (DPPC) and the dipalmitoyl-diacylglyceryl-N,N,N-trimethylhomoserine (DP-DGTS), we found that DP-DGTS bilayers are thicker than DPPC bilayers and therefore are more rigid. Furthermore, DP-DGTS bilayers are more repulsive, especially at long range, maybe due to unexpected unscreened electrostatic contribution. Finally, DP-DGTS bilayers could coexist in the gel and fluid phases.ConclusionThe different properties and hydration responses of PC and DGTS provide an explanation for the diversity of betaine lipids observed in marine organisms and for their disappearance in seed plants.

Molecular dynamics simulations of hydrophilic pores in phospholipid bilayers and Fe3O4 nanoparticles loaded with the 5-fluorouracil anticancer drug

The interaction of a PEGylated and non-PEGylated Fe3O4 nanoparticle drug-delivery system, with 5-fluorouracil (5-FU) as the chemotherapy drug, is investigated via atomistic molecular dynamics (MD). The induced pore formation in a dipalmitoylphosphatidylcholine (DPPC) bilayer phospholipid (BLPL) is studied, and the resulting hourglass-shaped pores with hydrophilic lipid headgroups lining the pores are observed. Furthermore, we optimize the required number of ligands that are required to allow for the formed pores to spontaneously reseal. Additionally, the number of water molecules that transverse through the water bridge is investigated. These results may be useful to design nanocarrier systems that will maintain the cellular osmotic pressure and stability, while the 5-FU is converted to the required metabolites inside the cell to serve its purpose as a chemotherapeutic drug.

LASER INDUCED CONFORMATIONAL CHANGES OF LIPIDS WITHIN MULTILAMELLAR VESICLES

"The biomedical potential of destabilizing liposomes through photoinduction relies on the use of near-infrared light, which offers inherent therapeutic advantages. Researchers have explored the effects of infrared laser light on dipalmitoyl phosphatidylcholine (DPPC) multilamellar vesicles, specifically investigating the interaction between the laser and zwitterionic dipalmitoyl phosphatidylcholine multilamellar vesicles using Fourier transform infrared spectroscopy and differential scanning calorimetry measurements. The results revealed that laser irradiation increased the number of gauche conformers and led to conformational changes within the acyl chains of the phospholipids. The transition temperature of lyophilized vesicles was also shifted to a lower temperature after laser irradiation, indicating that the laser had a dipalmitoyl phosphatidylcholine multilamellar significant effect on the acyl chains in the dipalmitoyl phosphatidylcholine bilayers and decreased the transition cooperativity of lipid acyl chains. These findings could aid in the development of more effective liposomal drug delivery systems by enhancing our understanding of the interaction between laser and lipid bilayers."

Phenylalanine and Tryptophan-Based Surfactants as New Antibacterial Agents: Characterization, Self-Aggregation Properties, and DPPC/Surfactants Vesicles Formulation.

Cationic surfactants based on phenylalanine (CnPC3NH3Cl) and tryptophan (CnTC3NH3Cl) were synthesized using renewable raw materials as starting compounds and a green synthetic procedure. The synthesis, acid-base equilibrium, aggregation properties, and antibacterial activity were investigated. Conductivity and fluorescence were used to establish critical micelle concentrations. Micellization of CnPC3NH3Cl and CnTC3NH3Cl occurred in the ranges of 0.42-16.2 mM and 0.29-4.6 mM, respectively. Since those surfactants have some acidic character, the apparent pKa was determined through titrations, observing increasing acidity with increasing chain length and being slightly more acidic with the phenylalanine than the tryptophan derivatives. Both families showed promising antibacterial efficacy against eight different bacterial strains. Molecular docking studies against the enzyme peptidoglycan glycosyltransferase (PDB ID:2OQO) were used to investigate the potential binding mechanism of target surfactant molecules. According to small angle X-ray scattering (SAXS) results, the surfactants incorporate into DPPC (Dipalmitoyl Phosphatidyl Choline) bilayers without strong perturbation up to high surfactant concentration. Some of the C12TC3NH3Cl/DPPC formulations (40%/60% and 20%/80% molar ratios) exhibited good antibacterial activity, while the others were not effective against the tested bacteria. The strong affinity between DPPC and surfactant molecules, as determined by the DFT (density functional theory) method, could be one of the reasons for the loss of antibacterial activity of these cationic surfactants when they are incorporated in vesicles.

Effect of xenon, an apolar general anaesthetic on the properties of the DPPC bilayer

The effect of xenon, a general anaesthetic, on the properties of the fully hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer is investigated by molecular dynamics simulations with two different force fields. Considering the well-known pressure reversal of the anaesthetic effect, we are looking for such changes that are reverted by the increase of the pressure, and hence can be relevant in explaining the molecular mechanism of general anesthesia. The results show that, besides its main preference for staying in the middle of the membrane, xenon also has a secondary preference for positions at the outer boundary of the hydrocarbon region, close to the crowded domain of the polar headgroups. This outer preference is a result of the interplay of the increasing attraction the xenon atoms experience and the decreasing free volume available for them upon going away from the middle of the membrane. It also turns out that any change that might be relevant in explaining the anaesthetic effect is related to xenon atoms staying in this outer preferred position. Since the model we employed does not account for the polarizability of the xenon atoms, and hence misses a part of the thermodynamic driving force of the preference for this outer position, all results should be considered as a lower bound estimate of the real effect. It is found that the xenon atoms induce a lateral swelling of the membrane by pushing the DPPC molecules farther away from each other, which, due to the insensitivity of the membrane thickness to the presence of xenon, naturally results in an increase of also the membrane volume. On the other hand, pressure increases the membrane thickness by increasing the order of the lipid tails, while it also causes a lateral shrinking of the bilayer. The net effect of these two opposite contributions is still a decrease of the membrane volume. In the light of these results, we propose to refine the 70 years old ‘critical volume hypothesis’ to a ‘critical surface area hypothesis’, claiming that general anesthesia occurs if the molar surface area of the membrane exceeds a critical value. Finally, the xenon-induced lateral swelling results in an increase of the empty space in the hydrocarbon region, allowing the DPPC molecules to move more freely, and hence increasing their lateral diffusion coefficient. All these changes are clearly reverted by pressure, and thus may well be relevant in respect of the molecular mechanism of general anesthesia.

Aggregation and partitioning of amyloid peptide fragments in the presence of a lipid bilayer: A coarse grained molecular dynamics study

Amyloidogenicity and toxicity of amyloid peptides have been linked to the peptide aggregation and interactions with lipid bilayers. In this work we used the coarse grained MARTINI model to study the aggregation and partitioning of amyloid peptide fragments Aβ(1–28) and Aβ(25–35) in the presence of a dipalmitoylphosphatidylcholine bilayer. We explored the peptide aggregation starting from three initial spatial arrangements where free monomers were placed in solution outside the membrane, at the membrane-solution interface, or in the membrane. We found that Aβ(1–28) and Aβ(25–35) interact with the bilayer quite differently. The Aβ(1–28) fragments show strong peptide-peptide and peptide-lipid interactions leading to irreversible aggregation where the aggregates stay confined to their initial spatial location. The Aβ(25–35) fragments show weaker peptide-peptide and peptide-lipid interaction leading to reversible aggregation and accumulation at the membrane-solution interface irrespective of their initial spatial arrangement. Those findings can be explained in terms of the shape of the potential of mean force for the single-peptide translocation across the membrane.

Regioselective Tip-Enhanced Raman Spectroscopy of Lipid Membranes with Sub-Nanometer Axial Resolution.

Noninvasive and label-free analysis of cell membranes at the nanoscale is essential to comprehend vital cellular processes. However, conventional analytical tools generally fail to meet this challenge due to the lack of required sensitivity and/or spatial resolution. Herein, we demonstrate that tip-enhanced Raman spectroscopy (TERS) is a powerful nanoanalytical tool to analyze dipalmitoylphosphatidylcholine (DPPC) bilayers and human cell membranes with submolecular resolution in the vertical direction. Unlike the far-field Raman measurements, TERS spectra of the DPPC bilayers reproducibly exhibited a uniquely shaped C-H band. These unique spectral features were also reproducibly observed in the TERS spectrum of human pancreatic cancer cells. Spectral deconvolution and DFT simulations confirmed that the TERS signal primarily originated from vibrations of the CH3 groups in the choline headgroup of the lipids. The reproducible TERS results obtained in this study unequivocally demonstrate the ultrahigh sensitivity of TERS for nanoanalysis of lipid membranes under ambient conditions.

Calorimetric, volumetric and structural studies of the interaction between chlorogenic acid and dipalmitoylphosphatidylcholine bilayers

Chlorogenic acid (CGA) is the main component of coffee and an antioxidant. CGA has been reported to bear various good health effects. At the same time, it has been found that the addition of CGA induces an undesirable deformation of red blood cells. This fact suggests that CGA may bind to the proteins or/and membrane lipids of red blood cells. This study aimed to examine how CGA binds the bilayers of phosphatidylcholine (PC), one of red blood cells' primary lipids. To this end, we investigated the effect of CGA on the phase behavior and the structure of dipalmitoyl-PC (DPPC) bilayers in the form of multi-lamellar vesicles. Calorimetry and dilatometry measurements showed that the DPPC chain melting transition cooperativity decreases as increasing CGA concentrations. In addition, X-ray diffraction results showed that the lamellar repeat periodicity becomes disordered, and the periodicity disappears completely at high CGA concentrations. Together with these findings, it can be inferred that the CGA molecules do not penetrate inside the DPPC bilayers but bind to their surface in a negatively charged form.

Spectral Characteristics and Functional Responses of Phospholipid Bilayers in the Terahertz Band.

Understanding the vibrational information encoded within the terahertz (THz) spectrum of biomolecules is critical for guiding the exploration of its functional responses to specific THz radiation wavelengths. This study investigated several important phospholipid components of biological membranes-distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylcholine (DPPC), sphingosine phosphorylcholine (SPH), and lecithin bilayer-using THz time-domain spectroscopy. We observed similar spectral patterns for DPPC, SPH, and the lecithin bilayer, all of which contain the choline group as the hydrophilic head. Notably, the spectrum of DSPE, which has an ethanolamine head group, was different. Interestingly, density functional theory calculations confirmed that the absorption peak common to DSPE and DPPC at approximately 3.0 THz originated from a collective vibration of their similar hydrophobic tails. Accordingly, the cell membrane fluidity of RAW264.7 macrophages with irradiation at 3.1 THz was significantly enhanced, leading to improved phagocytosis. Our results highlight the importance of the spectral characteristics of the phospholipid bilayers when studying their functional responses in the THz band and suggest that irradiation at 3.1 THz is a potential non-invasive strategy to increase the fluidity of phospholipid bilayers for biomedical applications such as immune activation or drug administration.

The interaction of tryptophan enantiomers with model membranes is modulated by polar head type and physical state of phospholipids

The mutual influence of chiral bioactive molecules and supramolecular assemblies is currently being studied in many research fields, including medical-pharmaceutical applications. Model membranes of phospholipids, such as the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the anionic dipalmitoylphosphatidylglycerol (DPPG), interact with a variety of chiral compounds that include amino acids. In this work, the interaction of tryptophan enantiomers, L-Trp and D-Trp, on DPPC and DPPG bilayers was investigated by using differential scanning calorimetry, attenuated total reflectance-Fourier transform infrared and spin-label electron spin resonance spectroscopies as well as molecular docking simulations. The results show that Trp enantiomers slightly perturb the bilayer thermotropic phase transitions. For both membranes, O atoms in the carbonyl groups have a propensity to act as acceptors of a (weak) hydrogen bond. The Trp chiral forms also promote formation of hydrogen bonds and/or hydration in the PO2– moiety of the phosphate group, especially for the DPPC bilayer. In contrast, they interact more closely with the glycerol group of DPPG polar head. Only for DPPC bilayers, both enantiomers increase the packing of the first hydrocarbon chain segments for temperatures through the gel state, whereas they do not affect the lipid chain order and mobility in the fluid state. The results are consistent with a Trp association in the upper region of the bilayers without permeation in the innermost hydrophobic region. The findings suggest that neutral and anionic lipid bilayers are differently sensitive to amino acid chirality.

Scaling Protein-Water Interactions in the Martini 3 Coarse-Grained Force Field to Simulate Transmembrane Helix Dimers in Different Lipid Environments.

Martini 3, the latest version of the widely used Martini force field for coarse-grained molecular dynamics simulations, is a promising tool to investigate proteins in phospholipid bilayers. However, simulating other lipid environments, such as detergent micelles, presents challenges due to the absence of validated parameters for their constituent molecules. Here, we propose parameters for the micelle-forming surfactant, dodecylphosphocholine (DPC). These result in micelle assembly with aggregation numbers in agreement with the experimental values. However, we identified a lack of hydrophobic interactions between transmembrane helix protein dimers and the tails of DPC molecules, preventing insertion and stabilization of the protein in the micelles. This problem was also observed for protein insertion by self-assembling 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or dipalmitoylphosphatidylcholine (DPPC) bilayers. We propose the reduction of the nonbonded interactions between protein and water beads by 10% as a simple and effective solution to this problem that enables protein encapsulation in phospholipid micelles and bilayers without altering protein dimerization or the bilayer structure.

The effects of adsorbed benzo(a)pyrene on dynamic behavior of polystyrene nanoplastics through phospholipid membrane: A molecular simulation study

Nanoplastics (NPs) are mainly generated from the decomposition of plastic waste and industrial production, which have attracted much attention due to the potential risk for humans. The ability of NPs to penetrate different biological barriers has been proved, but the understanding of molecular details is very limited, especially for organic pollutant-NP combinations. Here, we investigated the uptake process of polystyrene NPs (PSNPs) combined with benzo(a)pyrene (BAP) molecules by dipalmitoylphosphatidylcholine (DPPC) bilayers by molecular dynamics (MD) simulations. The results showed that the PSNPs can adsorb and accumulate BAP molecules in water phase and then carried BAP molecules to enter DPPC bilayers. At the same time, the adsorbed BAP promoted the penetration of PSNPs into DPPC bilayers effectively by hydrophobic effect. The process of BAP-PSNP combinations penetrating into DPPC bilayers can be summarized into four steps including adhesion on the DPPC bilayer surface, uptake by the DPPC bilayer, BAP molecules detached from the PSNPs, and the PSNPs depolymerized in the bilayer interior. Furthermore, the amount of adsorbed BAP on PSNPs affected the properties of DPPC bilayers directly, especially the fluidity of DPPC bilayers that determine the physiologic function. Obviously, the combined effect of PSNPs and BAP enhanced the cytotoxicity. This work not only presented a vivid transmembrane process of BAP-PSNP combinations and revealed the nature of the effects of adsorbed benzo(a)pyrene on the dynamic behavior of polystyrene nanoplastics through phospholipid membrane, but also provide some necessary information of the potential damage for organic pollutant-nanoplastic combinations on human health at a molecular level.

Assessing the role of membrane lipids in the action of ruthenium(III) anticancer compounds.

This work addresses the possible role of the cell membrane in the molecular mechanism of action of two salan-type ruthenium complexes that were previously shown to be active against human tumor cells, namely [Ru(III)(L1)(PPh3)Cl] and [Ru(III)(L2)(PPh3)Cl] (where L1 is 6,6'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol); and L2 is 2,2'-(1R,2R)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol)). One-component membrane models were first used, a disordered fluid bilayer of dioleoylphosphatodylcholine (DOPC), and an ordered rigid gel bilayer of dipalmitoylphosphatidylcholine. In addition, two quaternary mixtures of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and cholesterol were used to mimic the lipid composition either of mammalian plasma membrane (1:1:1:1mol ratio) or of a cancer cell line membrane (36.2:23.6:6.8:33.4mol ratio). The results show that both salan ligands L1 and L2 bind relatively strongly to DOPC bilayers, but without significantly affecting their structure. The ruthenium complexes have moderate affinity for DOPC. However, their impact on the membranes was notable, leading to a significant increase in the permeability of the lipid vesicles. None of the compounds compromised liposome integrity, as revealed by dynamic light scattering. Fluorescence spectroscopy studies revealed changes in the biophysical properties of all membrane models analyzed in the presence of the two complexes, which promoted an increased fluidity and water penetration into the lipid bilayer in the one-component systems. In the quaternary mixtures, one of the complexes had an analogous effect (increasing water penetration), whereas the other complex reorganized the liquid ordered and liquid disordered domains. Thus, small structural differences in the metal ligands may lead to different outcomes. To better understand the effect of these complexes in cancer cells, the membrane dipole potential was also measured. For both Ru complexes, an increase in the dipole potential was observed for the cancer cell membrane model, while no alteration was detected on the non-cancer plasma membrane model. Our results show that the action of the Ru(III) complexes tested involves changes in the biophysical properties of the plasma membrane, and that it also depends on membrane lipid composition, which is frequently altered in cancer cells when compared to their normal counterparts.

Understanding the transformations of nanoplastic onto phospholipid bilayers: Mechanism, microscopic interaction and cytotoxicity assessment

The ubiquitous nanoplastics are now considered emergent pollutants in environments. Bioaccumulation of nanoplastics is an important indicator of their hazard. In this work, molecular dynamics were used to study the uptake of five nanoplastics (polyvinyl chloride (PVC), polystyrene (PS), polylactic acid (PLA), polypropylene (PP), and polyethylene terephthalate (PET)) onto DPPC (dipalmitoylphosphatidylcholine) bilayers. Results suggest that nanoplastics became compact after they were deposited in the human body. For PET, PLA, and PS nanoplastics, a free energy barrier of 4–22 kcal mol−1 needed to be overcome to transfer these polymers from the interface region to the center of the DPPC bilayer. Besides, the free energy difference of PVC and PP from the bulk H2O to the surface of DPPC was −18.67 kcal mol−1 and −25.94 kcal mol−1, respectively. After uptake, the interaction between nanoplastics and lipid bilayer was dominated by the van der Waals rather than electrostatic interaction. Furthermore, the cytotoxicity of nanoplastics was also evaluated and it is reflected in their ability to decrease the thickness of the lipid bilayer. Overall, this work provides implications for understanding the bioaccumulation and toxicity of nanoplastic at the molecular level.

Effect of biphosphate salt on dipalmitoylphosphatidylcholine bilayer deformation by Tat polypeptide.

Translocation of positively charged cell penetrating peptides (CPP) through cell membrane is important in drug delivery. Here we report all-atom molecular dynamics simulations to investigate how a biphosphate salt in a solvent affects the interaction of a CPP, HIV-1 Tat peptide with model dipalmitoylphosphatidylcholine (DPPC) lipid bilayer. Tat peptide has a large number of basic arginines and a couple of polar glutamines. We observe that in absence of salt, the basic residues of the polypeptide get localized in the vicinity of the membrane without altering the bilayer properties much; polypeptide induce local thinning of the bilayer membrane at the area of localization. In presence of biphosphate salt, the basic residues, dressed by the biphosphate ions, are repelled by the phosphate head groups of the lipid molecules. However, polar glutamine prefers to stay in the vicinity of the bilayer. This leads to larger local bilayer thickness at the contact point by the polar residue and non-uniform bilayer thickness profile. The thickness deformation of bilayer structure disappears upon mutating the polar residue, suggesting importance of the polar residue in bilayer deformation. Our studies point to control bilayer deformation by appropriate peptide sequence and solvent conditions.

Theoretical insights into the uptake of sulfonamides onto phospholipid bilayers: Mechanisms, interaction and toxicity evaluation

Sulfonamides (SAs) are now recognized as the main emerging environmental pollutants in aquatic environments. Although the bioaccumulation capacities of SAs have been confirmed, the pathway for the penetration of the SAs into lipid bilayer has been not fully understood. In this study, the bioaccumulation mechanism of four typical SAs onto the dipalmitoyl phosphatidylcholine (DPPC) lipid bilayer and their effects on the properties of DPPC bilayer were employed and evaluated respectively by using molecular dynamics simulations. Results show that from the viewpoint of thermodynamics, it is favorable for these SAs partitioning to DPPC bilayer. The accommodation of four SAs onto the lipid membrane needs to undergo several processes, which include the contact stage, transformation stage, and absorption stage. Besides, the sulfamethoxazole (SMX) and sulfamethazine (SMZ) show a strong preference for the DPPC phase rather than the interface region while the sulfadiazine (SDZ) and sulfametoxydiazine (SMD) have similar tendencies in the interface region and DPPC phase. Furthermore, the cytotoxicity of SAs is reflected in their ability to affect the electrostatic potential of the membrane and to reduce the thickness of phospholipid bilayers. This molecular-level study provided an insightful understanding of the toxicity and bioaccumulation of SAs.

Interaction of Cyanine-D112 with Binary Lipid Mixtures: Molecular Dynamics Simulation and Differential Scanning Calorimetry Study.

This comprehensive molecular dynamics (MD) simulation and experimental study investigates the lipid bilayer interactions of dye D112 for potential photodynamic therapy (PDT) applications. PDT involves formation of a reactive oxidant species in the presence of a light sensitive molecule and light, interrupting cellular functions. D112 was developed as a photographic emulsifier, and we hypothesized that its combined cationic and lipophilic nature can render a superior photosensitizing property–crucial in various light therapies. The focus of this study is to elucidate the binding and insertion mechanisms of D112 with mixed lipid bilayers of anionic dipalmitoyl-phosphatidylserine (DPPS) and zwitterionic dipalmitoyl-phosphatidylcholine (DPPC) lipids to resemble cancer cell membranes. Our studies confirm initial electrostatic binding between the positively charged moieties of D112 and negatively charged lipid headgroups. Additionally, MD simulations combined with differential scanning calorimetry (DSC) studies confirm that D112-lipid interactions are governed by enthalpy-driven nonclassical hydrophobic effects in the membrane interior. It was further noted that despite the electrostatic preference of D112 toward the anionic lipids, D112 molecules colocalized on DPPC-rich domains after insertion. Atomistic level MD studies point toward two possible insertion mechanisms for D112: harpoon and flip. Further insights from the simulation showcase the interactions of low and high aggregates of D112 with the bilayer as the concentration of D112 increases in solution. The size of aggregates modulates the orientation and degree of insertion, providing important information for future studies on membrane permeation mechanisms.

Effect of Ionic Strength on Ibuprofenate Adsorption on a Lipid Bilayer of Dipalmitoylphosphatidylcholine from Molecular Dynamics Simulations.

In this work, the free energy change in the process of transferring ibuprofenate from the bulk solution to the center of a model of the dipalmitoylphosphatidylcholine bilayer at different NaCl concentrations was calculated. Two minima were found in the free energy profile: a local minimum, located in the vicinity of the membrane, and the global free energy minimum, found near the headgroup region. The downward shift of free energy minima with increasing NaCl concentration is consistent with the results of previous works. Conversely, the upward shift of the free energy maximum with increasing ionic strength is due to the competition of sodium ions and lipids molecules to coordinate with ibuprofenate and neutralize its charge. In addition, normal molecular dynamics simulations were performed to study the effects of the ibuprofenate on the lipid bilayer and in the presence of a high ibuprofenate concentration. The effect of ionic strength on the properties of the lipid bilayer and on lipid-drug interactions was analyzed. The area per lipid shrinking with increasing ionic strength, volume of lipids, and thickness of the bilayer is consistent with the experimental results. At a very high ibuprofenate concentration, the lipid bilayer dehydrates, and it consequently transforms into the gel phase, thus blocking the permeation.

Temperature- and Pressure-Induced Bilayer Phase Transitions of an Amide-Linked Phosphatidylcholine: A Contrasting Effect of Chain-Linkage Type

Abstract An unnatural phospholipid with two amide linkages, dipalmitoylamidodeoxyphosphatidylcholine (DPADPC), was synthesized and its bilayer phase transitions were observed by differential scanning calorimetry under atmospheric pressure and light-transmittance measurements under high pressure. The DPADPC bilayer membrane showed different phase transitions depending on the thermal history of the lipid sample under atmospheric pressure. The thermal-history dependent transitions were also observed under high pressure. The temperature–pressure phase diagram and thermodynamic quantities of the phase transitions of the DPADPC bilayer membrane were compared with those of bilayer membranes of hydrophobic chain-linkage isomers, ester-linked dipalmitoylphosphatidylcholine (DPPC) and ether-linked dihexadecylphosphatidylcholine (DHPC). The thermodynamic quantities of the main transition for these PC bilayer membranes were similar to one another, whereas the suppression of the interdigitation and great stabilization of the hydrated crystal phase were observed for the DPADPC bilayer membrane. Furthermore, the results of nuclear magnetic resonance measurements indicated that the motility of PC molecules in both gel and liquid crystal phases of the DPADPC bilayer membranes were much lower than those of the DPPC and DHPC bilayer membranes. From the above results, we concluded that the molecular interaction in the PC bilayer membranes increases in the order of ether-, ester- and amide-linkage isomers.