Computer simulations

To carry out the SMD simulations, first an all-atom simplified version of the block-copolymer system was constructed. This system consisted of 122 polymer chains, 50% of which were PLGA–PEG block-copolymers, whereas the rest were composed of pure PLGA chains. Next, the polymer chains were hydrated with water molecules⁵⁰, and a 40-ns trajectory of unbiased all-atom molecular dynamics simulations (uMD) was performed to equilibrate the entire system. The final stage of the uMD trajectory was used as the starting point for the SMD simulations. The entire system was positioned so that the direction of the reaction pathway (that is, the direction of the steered motion of the drug) was aligned along the Z-coordinate. To simplify the simulations, a generic drug-like aromatic compound, that is, phenanthrene, was used to replace Cy7. Different tail parts, CA, C12, OLA and PLGA2k were attached to phenanthrene to modify the overall drug properties along the lines of the experimental protocol. In the SMD simulation, each of these drug models was aligned along the Z-coordinate, and force was applied to move the drug models along the reaction coordinate that took them through the different phases of the hydrated block-copolymer systems. The SMD simulations employed the constant velocity algorithm implemented in the NAMD simulation package⁵¹ and CHARMM force field parameters⁵². The velocity was set to 0.0001 Å ps⁻¹ for all the drug models, and the force constant was set to 7.0 kcal mol⁻¹ Å⁻¹ along the direction of the Z-coordinate. A Langevin thermostat and piston were used to maintain the temperature at 300 K and the pressure at 1 atm⁵³.