The effect of the core substituent structure on the micellar behavior of thermoresponsive amphiphilic poly(εcaprolactone) diblock copolymer micelles was investigated through a combination of experimental and computational methods. The polycaprolactone (PCL) amphiphilic block copolymers used in this study consisted of a hydrophilic poly{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} block, which also endowed the polymer with thermoresponsiveness, and various hydrophobic poly(γ-alkoxy-ε-caprolactone) blocks. Five different substituents have been attached to the γ-position of the ε-caprolactone of the hydrophobic block, namely octyloxy, ethylhexyloxy, ethoxy, benzyloxy, and cyclohexylmethoxy, which self-assembled in aqueous media to generate the core of the micelles. All five synthesized diblock copolymers formed micelles in water and displayed thermoresponsive behavior with lower critical solution temperature (LCST) in the range of 36−39 °C. The impact of different substituents on the micelle properties such as size, stability, and phase transition behavior was investigated. Drug loading and release properties were also studied by employing doxorubicin (DOX) as payload. Molecular dynamics modeling was used to predict the variation of particle size, free volume, and drug loading capacity. The drug loading capacity predicted from molecular dynamics simulation was found to be comparable with the experimental data, which suggests that molecular dynamic simulations may be a useful tool to provide valuable selection criteria for the engineering of polymeric micelles with tunable size and drug loading capacity.
The localization of nanoparticles (NPs) at fluid/fluid interfaces has emerged as an effective self-assembly method. To understand the fundamentals of this localization mechanism, it is necessary to quantify the physical behavior of NPs in the vicinity of a fluid interface. Conventional theories treat the NP as a rigid object whose equilibrium position is dictated by the balance of its surface tensions with the two fluids. However, most NPs are functionalized with “soft” organic surface layers which play a large role in determining the shape of the NP. Through molecular dynamics simulations, we show that the functionalizing layer also greatly alters the interfacial behavior of the NP beyond the scope of common theory. Furthermore, we characterize the effect of the surface density of functionalizing molecules on the NP deformability. Our results have implications on the experimental interpretation of NP contact angles and may be useful for future theory development.
In Förster resonance energy transfer (FRET) experiments, extracting accurate structural information about macromolecules depends on knowing the positions and orientations of donor and acceptor fluorophores. Several approaches have been employed to reduce uncertainties in quantitative FRET distance measurements. Fluorophore-position distributions can be estimated by surface accessibility (SA) calculations, which compute the region of space explored by the fluorophore within a static macromolecular structure. However, SA models generally do not take fluorophore shape, dye transition-moment orientation, or dye-specific chemical interactions into account. We present a detailed molecular-dynamics (MD) treatment of fluorophore dynamics for an ATTO donor/acceptor dye pair and specifically consider as case studies dye-labeled protein-DNA intermediates in Cre site-specific recombination. We carried out MD simulations in both an aqueous solution and glycerol/water mixtures to assess the effects of experimental solvent systems on dye dynamics. Our results unequivocally show that MD simulations capture solvent effects and dye-dye interactions that can dramatically affect energy transfer efficiency. We also show that results from SA models and MD simulations strongly diverge in cases where donor and acceptor fluorophores are in close proximity. Although atomistic simulations are computationally more expensive than SA models, explicit MD studies are likely to give more realistic results in both homogeneous and mixed solvents. Our study underscores the model-dependent nature of FRET analyses, but also provides a starting point to develop more realistic in silico approaches for obtaining experimental ensemble and single-molecule FRET data.
The use of gene therapeutics, including short interfering RNA (siRNA), is limited by the lack of efficient delivery systems. An appealing approach to deliver gene therapeutics involves noncovalent complexation with cell penetrating peptides (CPPs) which are able to penetrate the cell membranes of mammals. Although a number of CPPs have been discovered, our understanding of their complexation and translocation of siRNA is as yet insufficient. Here, we report on computational studies comparing the binding affinities of CPPs with siRNA, considering a variety of CPPs. Specifically, seventeen CPPs from three different categories, cationic, amphipathic, and hydrophobic CPPs, were studied. Molecular mechanics were used to minimize structures, while molecular docking calculations were used to predict the orientation and favorability of sequentially binding multiple peptides to siRNA. Binding scores from docking calculations were highest for amphipathic peptides over cationic and hydrophobic peptides. Results indicate that initial complexation of peptides will likely occur along the major groove of the siRNA, driven by electrostatic interactions. Subsequent binding of CPPs is likely to occur in the minor groove and later on bind randomly, to siRNA or previously bound CPPs, through hydrophobic interactions. However, hydrophobic CPPs do not show this binding pattern. Ultimately binding yields a positively charged nanoparticle capable of noninvasive cellular import of therapeutic molecules.
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