Analysis of the conformational properties of amine ligands at the gold/water interface with QM, MM and QM/MM simulations.

We describe a strategy of integrating quantum mechanical (QM), hybrid quantum mechanical/molecular mechanical (QM/MM) and MM simulations to analyze the physical properties of a solid/water interface. This protocol involves using a correlated ab initio (CCSD(T)) method to first calibrate Density Functional Theory (DFT) as the QM approach, which is then used in QM/MM simulations to compute relevant free energy quantities at the solid/water interface using a mean-field approximation of Yang et al. that decouples QM and MM thermal fluctuations; gas-phase QM/MM and periodic DFT calculations are used to determine the proper QM size in the QM/MM simulations. Finally, the QM/MM free energy results are compared with those obtained from MM simulations to directly calibrate the force field model for the solid/water interface. This protocol is illustrated by examining the orientations of an alkyl amine ligand at the gold/water interface, since the ligand conformation is expected to impact the chemical properties (e.g., charge) of the solid surface. DFT/MM and MM simulations using the INTERFACE force field lead to consistent results, suggesting that the effective gold/ligand interactions can be adequately described by a van der Waals model, while electrostatic and induction effects are largely quenched by solvation. The observed differences among periodic DFT, QM/MM and MM simulations, nevertheless, suggest that explicitly including electronic polarization and potentially charge transfer in the MM model can be important to the quantitative accuracy. The strategy of integrating multiple computational methods to cross-validate each other for complex interfaces is applicable to many problems that involve both inorganic/metallic and organic/biomolecular components, such as functionalized nanoparticles.

Quantifying the Electrostatics of Polycation-Lipid Bilayer Interactions.

Mechanistic insight into how polycations disrupt and cross cell membranes is needed for understanding and controlling polycation-membrane interactions, yet such information is surprisingly difficult to obtain at the molecular level. We use second harmonic and vibrational sum frequency generation spectroscopies along with quartz crystal microbalance with dissipation monitoring and computer simulations to quantify the interaction of poly(allylamine) hydrochloride (PAH) and its monomeric precursor allylamine hydrochloride (AH) with lipid bilayers. We find PAH adsorption to be reversible and nondisruptive to the bilayer under the conditions of our experiments. With an observed free adsorption energy of -52.7 ± 0.6 kJ/mol, PAH adsorption was found to be surprisingly less favorable relative to AH (-14.6 ± 0.4 kJ/mol) when considering a simple additive model. By experimentally quantifying the number of adsorbates and the average amount of charge carried by each adsorbate, we find that the PAH is associated with only 70% of the positive charges it could hold while the AH remains mostly charged while attached to the membrane. Simulations indicate that PAH pulls in condensed counterions from solution to avoid charge-repulsion along its backbone and with other PAH molecules to attach to, and completely cover, the bilayer surface. In addition, computations indicate that the amine groups shift their pKa values due to the confined environment upon adsorption to the surface. Our results provide experimental constraints for theoretical calculations, which yield atomistic views of the structures that are formed when polycations interact with lipid membranes that will be important for predicting polycation-membrane interactions.

Embryonic diapause due to high glucose is related to changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism.

Introduction: The adverse effects of high glucose on embryos can be traced to the preimplantation stage. This study aimed to observe the effect of high glucose on early-stage embryos. Methods and results: Seven-week-old ICR female mice were superovulated and mated, and the zygotes were collected. The zygotes were randomly cultured in 5 different glucose concentrations (control, 20mM, 40mM, 60mM and 80mM glucose). The cleavage rate, blastocyst rate and total cell number of blastocyst were used to assess the embryo quality. 40 mM glucose was selected to model high glucose levels in this study. 40mM glucose arrested early embryonic development, and the blastocyst rate and total cell number of the blastocyst decreased significantly as glucose concentration was increased. The reduction in the total cell number of blastocysts in the high glucose group was attributed to decreased proliferation and increased cell apoptosis, which is associated with the diminished expression of GLUTs (GLUT1, GLUT2, GLUT3). Furthermore, the metabolic characterization of blastocyst culture was observed in the high-glucose environment. Discussion: The balance of glycolysis and oxidative phosphorylation at the blastocyst stage was disrupted. And embryo development arrest due to high glucose is associated with changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism.

A phthalocyanine-based self-assembled nanophotosensitizer for efficient in vivo photodynamic anticancer therapy.

To develop highly efficient photosensitizers for photodynamic therapy, herein a zinc(II) phthalocyanine-folate conjugate (PcN-FA) used to construct an activatable nanophotosensitizer (NanoPcN-FA) through a facile self-assembly. The self-assembled nanophotosensitizer (NanoPcN) without folate-modification was used as a negative control. After self-assembly, the photoactivities of NanoPcN-FA was quenched. The in vitro studies showed that NanoPcN-FA could be taken in by folate-receptor (FR)-positive SKOV3 cells and activated in the cells. It also exhibited slightly higher photocytotoxicity against SKOV3 cells than NanoPcN. Moreover, the competitive assay confirmed that the cellular uptake of NanoPcN-FA was through a FR-mediated process. Finally, the in vivo results indicated that NanoPcN-FA could target tumor tissue of S180 rat ascitic tumor-bearing mice due to the folic acid (FA) ligand, leading to a highly efficient antitumor photodynamic efficacy with the tumor inhibition rate of 95%.