In this paper, we present a computational model of the adsorption and percolation mechanism of poloxamers (poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) triblock copolymers) across a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer. A coarse-grained model was used to cope with the long time scale of the percolation process. The simulations have provided details of the interaction mechanism of Pluronics with lipid bilayer. In particular, the results have shown that polymer chains containing a PPO block with a length comparable to the DMPC bilayer thickness, such as P85, tends to percolate across the lipid bilayer. On the contrary, Pluronics with a shorter PPO chain, such as L64 and F38, insert partially into the membrane with the PPO block part while the PEO blocks remain in water on one side of the lipid bilayer. The percolation of the polymers into the lipid tail groups reduces the membrane thickness and increases the area per lipid. These effects are more evident for P85 than L64 or F38. Our findings are qualitatively in good agreement with published small-angle X-ray scattering experiments that have evidenced a thinning effect of Pluronics on the lipid bilayer as well as the role of the length of the PPO block on the permeation process of the polymer through the lipid bilayer. Our theoretical results complement the experimental data with a detailed structural and dynamic model of poloxamers at the interface and inside the lipid bilayer.

Herein, we report a comparative modelling study of 1,2-dimethoxyethane (DME) and 1,2-dimethoxypropane (DMP) at 298 K and 318 K in the liquid state, water mixtures, and at infinite dilution condition in water, methanol, carbon tetrachloride, and n-heptane. Both DME and DMP are united-atom models compatible with GROMOS∕OPLS force fields. Calculated thermodynamic and structural properties of the pure DME and DMP liquids resulted in excellent agreement with the experimental data. In aqueous solutions, densities, diffusion coefficients, and concentration dependent conformers of DME, were in agreement with experimental data. The calculated free energy of solvation (ΔG(hyd)) at 298 K is equal to -22.1 ± 0.8 kJ mol(-1) in good agreement with the experimental value of 20.2 kJ mol(-1). In addition, the free energy of solvation of DME in non-aqueous solvents follows the trend methanol ≈ water < carbon tetrachloride < n-heptane, consistently with the dielectric constant of the solvents. On contrary, the presence of an extra methyl group on chiral carbon makes DMP less soluble than DME in water (ΔG(hyd) = -16.0 ± 1.1 kJ mol(-1)) but more soluble in non-polar solvents as n-heptane. Finally, for the DMP the chiral discrimination of the two enantiomers was calculated as solvation free energy difference of one DMP isomer in the solution of the other. The obtained value of ΔΔG(RS) = -3.7 ± 1.4 kJ mol(-1) indicates a net chiral discrimination of the two enantiomers.

In this paper, the conformation and dynamics properties of polyethylene oxide (PEO) and polypropylene oxide (PPO) polymer chains at 298 K have been studied in the melt and at infinite dilution condition in water, methanol, chloroform, carbon tetrachloride, and n-heptane using molecular dynamics simulations. The calculated density of PEO melt with chain lengths of n = 2, 3, 4, 5 and, for PPO, n = 7 are in good agreement with the available experimental data. The conformational properties of PEO and PPO show an increasing gauche preference for the O-C-C-O dihedral in the following order water>methanol>chloroform>carbon tetrachloride = n-heptane. On the contrary, the preference for trans conformation has a maximum in carbon tetrachloride and n-heptane followed in the order by chloroform, methanol, and water. The PEO conformational preferences are in qualitative agreement with results of NMR studies. PEO chains formed different types of hydrogen bonds with polar solvent molecules. In particular, the occurrence of bifurcated hydrogen bonding in chloroform was also observed. Radii of gyration of PEO chains of length larger than n = 9 monomers showed a good agreement with light scattering data in water and in methanol. For the shorter chains the observed deviations are probably due to the enhanced hydrophobic effects caused by the terminal methyl groups. For PEO the fitting of end-to-end distance distributions with the semi-flexible chain model at 298 K provided persistence lengths of 0.375 and 0.387 nm in water and methanol, respectively. Finally, the radius of gyration of Pluronic P85 turned out to be 2.25 ± 0.4 nm at 293 K in water in agreement with experimental data.

In this paper, a theoretical study of 1,2-dimethoxyethane (DME) and 1,2-dimethoxypropane (DMP) at water/n-heptane and 1,2-dimyristoyl-sn-glycero-3-phospatidycholine (DMPC) lipid bilayer/water interfaces using the umbrella sampling method is reported. Recently proposed GROMOS96/OPLS compatible models for DME and DMP have been used for the simulation studies. The percolation free energy barrier of one DME and DMP molecule from water to n-heptane phase calculated using the umbrella sampling method turned out to be equal to ~18.5 kJ/mol and ~6 kJ/mol, respectively. In the case of the DMPC lipid bilayer, overall free energy barriers of ~20 kJ/mol and ∼12 kJ/mol were obtained for DME and DMP, respectively. The spontaneous diffusion of DME and DMP in the lipid bilayer has also been investigated using unconstrained molecular dynamics simulations at the water/DMPC interface and inside the lipid bilayer. As expected from the estimated percolation barriers, simulation results show that DME, contrary to DMP, spontaneously diffuse into the aqueous solution from the lipid interior. In addition, simulations with multiple DME or DMP molecules at the interface show spontaneous diffusion within 50 ns inside the DMPC layer only for DMP.

Curcumin, a naturally occurring drug molecule, has been extensively investigated for its various potential usages in medicine. Its water insolubility and high metabolism rate require the use of drug delivery systems to make it effective in the human body. Among various types of nanocarriers, block copolymer based ones are the most effective. These polymers are broadly used as drug-delivery systems, but the nature of this process is poorly understood. In this paper, we propose a molecular dynamics simulation study of the interaction of Curcumin with block copolymer based on polyethylene oxide (PEO) and polypropylene oxide (PPO). The study has been conducted considering the smallest PEO and PPO oligomers and multiple chains of the block copolymer Pluronic P85. Our study shows that the more hydrophobic 1,2-dimethoxypropane (DMP) molecules and PPO block preferentially coat the Curcumin molecule. In the case of the Pluronic P85, simulation shows formation of a drug-polymer aggregate within 50 ns. This process leaves exposed the PEO part of the polymers, resulting in better solvation and stability of the drug in water.