[Show abstract][Hide abstract] ABSTRACT: Ionic liquids (ILs) are considered to be green solvents because of their non-volatility. Although
ILs are relatively safe in the atmospheric environment, they may be toxic in other environments.
Our previous research showed that the cytotoxicity of ILs to biological organisms is attributable
to interference with cell membranes by IL insertion. However, the effects of ILs on ion channels,
which play important roles in cell homeostasis, have not been comprehensively studied to date.
In this work, we studied the interactions between ILs and lipid bilayer membranes with gramicidin
A ion channels. We used two methods, namely electrical and fluorescence measurements of ions
that permeate the membrane. The lifetimes of channels were increased by all the ILs tested in this
work via stabilizing the compressed structure of the lipid bilayer and the rate of ion flux through
gA channels was decreased by changing the membrane surface charge. The former effect, which
increased the rate of ion flux, was dominant at high salt concentrations, whereas the latter, which
decreased the rate of ion flux, was dominant at low salt concentrations. The effects of ILs increased
with increasing concentration and alkyl chain length. The experimental results were further studied
using molecular dynamics simulations.
[Show abstract][Hide abstract] ABSTRACT: Imidazolium-based ionic surfactants with hydrocarbon tails of different sizes were simulated with lipid bilayers at different salt concentrations. Starting with the random position of ionic surfactants outside the bilayer, surfactants with long tails mostly insert into the bilayer, while those with short tails show the insertion of fewer surfactant molecules, indicating the effect of the tail length. In particular, surfactants with the tail of two or four hydrocarbons insert and reversibly detach from the bilayer, while the inserted longer surfactants cannot be reversibly detached because of the strong hydrophobic interaction with lipid tails, in quantitative agreement with experiments. Longer surfactants more deeply and irreversibly insert into the bilayer and thus increase lateral diffusivities of the bilayer, indicating that longer surfactants more significantly disorder lipid bilayers, which also agrees with experiments regarding the effect of the tail length of ionic surfactants on membrane permeability and toxicity. Addition of NaCl ions weakens the electrostatic interactions between head groups of surfactants and lipids, leading to the binding of fewer surfactants into the bilayer. In particular, our simulation findings indicate that insertion of ionic surfactants can be initiated by either the hydrophobic interaction between tails of surfactants and lipids or the electrostatic binding between imidazolium heads and lipid heads, and the strength of hydrophobic and electrostatic interactions depends on the tail length of surfactants.
No preview · Article · Jan 2015 · Physical Chemistry Chemical Physics
[Show abstract][Hide abstract] ABSTRACT: We performed coarse-grained molecular dynamics simulations of antimicrobial peptides PGLa and magainin 2 in lipid bilayers. PGLa peptides or mixtures of PGLa and magainin 2 were initially widely spaced or clustered above the bilayer surface with different heterodimeric orientations (parallel or antiparallel). Simulations show that the presence of magainin 2 promotes more tilting and insertion of PGLa into the bilayer, indicating the synergistic effect. Magainin 2 interact with lipid headgroups and thus stay horizontally on the bilayer surface, while PGLa insert into the bilayer, leading to more tilted conformation, in agreement with recent NMR experiments. In particular, for the systems with the initially antiparallel-oriented heterodimers or with the neutrally mutated magainin 2, much fewer parallel heterodimers form, and PGLa peptides are less tilted and inserted, indicating that the formation of parallel heterodimers is important for the PGLa insertion, as suggested in experiments. Peptides aggregate in the mixture of PGLa and magainin 2, but not in the system without magainin 2, indicating that magainin 2 induce the peptide aggregation, which is required for the pore formation. These simulation findings agree with the experimental observations of the heterodimer formation as well as different positions of PGLa and magainin 2 in the bilayer, which seem to conflict. These conflicting results can be explained by the synergistic mechanism that magainin 2 form parallel heterodimers with PGLa and induce the aggregation of heterodimers, leading to the formation of pores, where magainin 2 tend to interact with the bilayer surface, while PGLa are tilted and inserted into the hydrophobic region of the bilayer.
[Show abstract][Hide abstract] ABSTRACT: One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation.
[Show abstract][Hide abstract] ABSTRACT: We performed coarse-grained (CG) molecular dynamics simulations of trimeric α-helical coiled coils grafted with polyethylene glycol (PEG) of different sizes and conjugate positions, and the self-assembled micelle of amphiphilic trimers. The CG model for the trimeric coiled coil is verified by comparing the α-helical structure and interhelical distance with those calculated from all-atom simulations. In CG simulations of PEGylated trimers, end-to-end distances and radii of gyration of PEGs grafted to the side of peptides become smaller than those of free PEGs in water, which agree with experiments. This smaller size of the grafted PEGs is also confirmed by calculating the thickness of the PEG layer, which is smaller than the size of the mushroom. These indicate the adsorption of PEG chains onto coiled coils, since hydrophobic residues in the exterior sites of coiled coils tend to be less exposed to water and thus interact with PEGs, leading to the compact conformation of adsorbed PEGs. Simulations of the self-assembly of amphiphilic trimers show that the randomly distributed trimers self-assemble to micelles. The outer radius and hydrodynamic radius of the micelle, which were calculated respectively from radial densities and diffusion coefficients, are ~7 nm, in agreement with the experimental value of ~7.5 nm, while the aggregation number of amphiphilic molecules per micelle is lower than the experimentally proposed value. These simulations predict the experimentally measured size of PEGs grafted to the trimeric coiled coils and their self-assembled amphiphilic micelles, as well as suggest that the aggregation number of the micelle may be smaller, which needs to be confirmed by experiments.
[Show abstract][Hide abstract] ABSTRACT: Single-walled carbon nanotubes (SWNTs) covalently functionalised with polyethylene glycol (PEG) or noncovalently coated with PEGylated lipids were simulated in water and in lipid bilayers at different PEG sizes and grafting densities using coarse-grained force fields. Starting with the random position of three SWNT-PEG complexes in water, larger PEGs at higher grafting densities more significantly inhibit the aggregation of SWNTs because of larger radii of gyration and hydrodynamic radii of the SWNT-PEG complex, which influence the thickness and the wrapping extent of PEG layer. In particular, PEG-functionalised SWNTs, where PEGs are evenly grafted along the SWNT, disperse, while PEG-coated SWNTs aggregate because SWNTs are less covered by randomly adsorbed PEGylated lipids. Simulations of SWNT-PEGs in lipid bilayers show that PEG (Mw = 550 and 2000)-functionalised SWNTs bind to the bilayer surface but do not insert into the bilayer, while PEG-coated SWNTs insert into the bilayer because PEGylated lipids detach from SWNTs and mix with bilayer lipids. These findings support recent experiments at the same PEG size and density, which suggested that PEG-coated SWNTs may form bundles and thus cannot be easily excreted through the renal route, while PEG-functionalised SWNTs may remain individual and thus show more renal excretion.
No preview · Article · May 2014 · Molecular Simulation
[Show abstract][Hide abstract] ABSTRACT: Polyethylene glycol (PEG) has been conjugated to many drugs or drug carriers to increase their solubility and circulating lifetime, and reduce toxicity. This has motivated many experimental studies to understand the effect of PEGylation on delivery efficiency. To complement the experimental findings and uncover the mechanism that cannot be captured by experiments, all-atom and coarse-grained molecular dynamics (MD) simulations have been performed. This has become possible, due to recent advances in simulation methodologies and computational power. Simulations of PEGylated peptides show that PEG chains wrap antimicrobial peptides and weaken their binding interactions with lipid bilayers. PEGylation also influences the helical stability and tertiary structure of coiled-coil peptides. PEGylated dendrimers and single-walled carbon nanotubes (SWNTs) were simulated, showing that the PEG size and grafting density significantly modulate the conformation and structure of the PEGylated complex, the interparticle aggregation, and the interaction with lipid bilayers. In particular, simulations predicted the structural transition between the dense core and dense shell of PEGylated dendrimers, the phase behavior of self-assembled complexes of lipids, PEGylated lipids, and SWNTs, which all favorably compared with experiments. Overall, these new findings indicate that simulations can now predict the experimentally observed structure and dynamics, as well as provide atomic-scale insights into the interactions of PEGylated complexes with other molecules.
[Show abstract][Hide abstract] ABSTRACT: Lipid bilayers, which consist of dipalmitoylglycerophosphocholines (DPPCs), PEGylated lipids, cholesterols, and elastin-like polypeptides (ELPs; [VPGVG]3) at different molar ratios, were simulated. Simulations were carried out for 2 μs using the coarse-grained (CG) model that had captured the experimentally observed phase behavior of PEGylated lipids and lateral diffusivity of DPPC bilayers. Starting with the initial position of ELPs on the bilayer surface, ELPs insert into the hydrophobic region of the bilayer because of their interaction with lipid tails, consistent with previous all-atom simulations. Lateral diffusion coefficients of DPPCs significantly increase in the bilayer composed of more ELPs and less cholesterols, showing their opposite effects on the bilayer dynamics. In particular, ELPs modulate the dynamics and phase for the disordered liquid bilayer, but not for the ordered gel bilayer, indicating that ELPs can destabilize only the disordered bilayer. In the ordered bilayer, ELP chains tend to have a spherical shape and slowly diffuse, while they are extended and diffuse faster in the disordered bilayer, indicating the effect of the bilayer phase on the conformation and diffusivity of ELPs. These findings explain the experimental observation that the ELP-conjugated liposomes are stable at 310 K (ordered phase) but become unstable and release the encapsulated drugs at 315 K (disordered phase), which suggests the effects of ELPs and cholesterols. Since the cholesterol-stabilized bilayer can be destabilized by the extended shaped ELPs only in the disordered phase (not in the ordered phase), the inclusion of cholesterols is required to safely shield drugs at 310 K as well as allow ELPs to disrupt lipids and destabilize the liposomes at 315 K.
No preview · Article · Jan 2014 · Physical Chemistry Chemical Physics
[Show abstract][Hide abstract] ABSTRACT: Single-walled carbon nanotubes (SWNTs) covalently or noncovalently modified with polyethylene glycol (PEG) of different sizes (Mw = 550, 2000, 5000, and 7000) and grafting densities (5–16 PEGs per SWNT) were simulated using coarse-grained force fields. The covalently grafted PEGs are evenly distributed on SWNTs, while the noncovalently PEGylated SWNTs show the random distribution of PEGylated lipids adsorbed to the SWNT, in which the SWNT sidewall is less completely wrapped by PEGs and thus largely exposed to water, as was observed in experiments. For covalently PEGylated SWNTs, longer PEG chains with higher grafting density yield a larger size, more isotropic shape, and lower diffusivity of the SWNT–PEG complex. In particular, at low grafting density, the thickness of the PEG layer on SWNTs nearly equals the size of the mushroom, where the end-to-end distance of PEGs is smaller than the distance between the grafting points, similar to the conformation of an isolated chain in water. However, at high grafting density, the thickness of the PEG layer increases beyond the mushroom regime, indicating a mushroom-to-brush transition, in agreement with the Alexander–de Gennes theory. These findings indicate that the PEGylation method influences the distribution of PEG chains on SWNTs and that the PEG size and grafting density modulate the conformation of the conjugated PEG chains, which helps explain the experimentally proposed transition of the PEG conformation between mushroom and brush.
No preview · Article · Nov 2013 · The Journal of Physical Chemistry C
[Show abstract][Hide abstract] ABSTRACT: Bax-α5 and Bcl-xL-α5, which are shorter versions of apoptosis-regulating proteins Bax and Bcl-xL, were simulated with lipid bilayers composed of pure dioleoylglycerophosphocholine (DOPC) lipids or a mixture of DOPCs and cholesterols. Starting with the initial peptide position near the bilayer surface, both Bax-α5 and Bcl-xL-α5 bind to the bilayer because of their charge interactions with lipid head groups. After binding to the bilayer surface, Bax-α5 inserts into the pure DOPC bilayer, but not into the DOPC-cholesterol bilayer, showing the effect of cholesterols on the peptide-bilayer interaction. Despite the similar peptide structure, Bcl-xL-α5 does not insert into the bilayer, in contrast to the interaction of Bax-α5 with the bilayer. Bcl-xL-α5 predominantly has the random-coil structure in both aqueous and membrane environments, while Bax-α5 shows a higher extent of α-helical structure in the bilayer than in water, in quantitative agreement with experiment. In particular, although Bax-α5 and Bcl-xL-α5 have the same extent of the electrostatic interaction with lipid head groups, Bax-α5 has stronger hydrophobic interaction with lipid tails than does Bcl-xL-α5. These indicate that Bax-α5 retains α-helical structure, where hydrophobic residues on one side of the α-helix interact with lipid tails and thus can easily attract the peptide into the lipid-tail region, while Bcl-xL-α5 forms a random coil that tends to spread on the bilayer surface and thus has weaker hydrophobic interaction with lipid tails. Our findings help explain the experimental observation that showed that Bax-α5 disorders lipids and induces pore formation, but Bcl-xL-α5 does not.
No preview · Article · Nov 2013 · Physical Chemistry Chemical Physics
[Show abstract][Hide abstract] ABSTRACT: Polyethylene glycol (PEG)-grafted magainin 2 and tachyplesin I were simulated with lipid bilayers. In the simulations of PEGylated magainin 2 and tachyplesin I in water, both peptides are wrapped by PEG chains. The α-helical structure of PEGylated magainin 2 is broken in water, while β-sheet of PEGylated tachyplesin I keeps stable, similar to the structural behavior of unPEGylated peptides, in agreement with experiments. Simulations of PEGylated peptides with lipid bilayers show that PEG chains block the electrostatic interaction between cationic residues of peptides and anionic phosphates of lipids, leading to the less binding of the peptide to the bilayer surface, which is observed more significantly for magainin 2 than for tachyplesin I. Since the random-coiled magainin 2 can be more completely covered by PEGs than does the β-sheet tachyplesin I, the PEGylation effect on the decreased binding is larger for magainin 2, showing the dependence of PEGylation on the peptide structure. These simulation findings qualitatively support the experimental observation of the different extents of the reduced membrane-permeabilizing activity for PEGylated magainin 2 and tachyplesin I.
[Show abstract][Hide abstract] ABSTRACT: We performed coarse-grained (CG) molecular dynamics (MD) simulations of single-walled carbon nanotubes (SWNTs) with lipid bilayers to understand the effect of the SWNT diameter, length, and concentration on membrane curvature and penetration. Starting with different orientations of multiple SWNTs near lipid bilayers, simulations show that SWNTs insert into the bilayer and induce membrane curvature, which is much larger than that observed from previous simulations of a single SWNT. Longer and thicker SWNTs at higher concentration cause larger membrane curvature, indicating the effect of the SWNT size and concentration, in qualitative agreement with experiments. In particular, thicker SWNTs significantly increase the bilayer height and the difference of the projected and contour bilayer areas, decrease the area compressibility, and disorder lipids. When inserted into the bilayer, thinner SWNTs mainly contact the entire tails of lipids, while thicker SWNTs are wrapped mainly by the ending tail-carbons, leading to the larger membrane curvature. This indicates the effect of SWNT diameter on the SWNT-lipid interaction, yielding different extents of membrane curvature. These findings imply that the SWNT-induced membrane penetration and curvature are modulated by a combination of SWNT length, diameter, and concentration.
No preview · Article · Sep 2013 · Physical Chemistry Chemical Physics
[Show abstract][Hide abstract] ABSTRACT: The conformational effects of lysine-rich peptides on the biomineralization of TiO2 were investigated. The biomineralization activity of the peptide was dependent on the spatial proximity of the amino groups, which is determined by the secondary structure.
No preview · Article · Aug 2013 · Dalton Transactions
[Show abstract][Hide abstract] ABSTRACT: Heparin decomplexation experiments, as well as all-atom (AA) and coarse-grained (CG) molecular dynamics (MD) simulations were performed to determine the effect of the size of arginine(Arg)-rich peptides on the structure and binding strength of the siRNA-peptide complex. At a fixed peptide/siRNA mole ratio of 5:1 or 10:1, the siRNA complexes with peptides longer than 9 Arg residues are more easily decomplexed by heparin than are those with 9 Arg residues. At these mole ratios, peptides longer than 9 Arg residues have cationic/anionic charge ratios in excess of unity, and produce more weakly bound complexes than 9-Arg residue ones do. AA simulations of mixtures of peptides with a single siRNA show formation of an electrostatically-induced complex, and the longer peptides produce a larger complex, but with no significant increase in the number of Arg residues bound to the siRNA. Larger-scale CG-MD simulations show that multiple siRNAs can be linked together by peptides into a large complex, as observed in the experiments. The peptides longer than 9 residues, which at mole ratio 5:1 yield a peptide/siRNA charge ratio in excess of unity, include many non-interacting Arg residues, which repel each other electrostatically. This leads to a less dense complex than for 9-residue peptides, which can explain why these longer complexes are more easily decomplexed by heparin molecules, as observed in the experiments. The key role of the charge ratio is supported by simulations that show that at a mole ratio of 2.5 peptides per siRNA, the longer 18-residue peptide has a charge ratio of roughly unity, and also shows a tight complex, just as the 9-residue peptide does at a 5:1 mole ratio, where its charge ratio is also unity.
No preview · Article · May 2013 · The Journal of Physical Chemistry B