Insight into the Assembling Mechanism of Cryptococcus Capsular Glucuronoxylomannan Based on Molecular Dynamics Simulations.

Cryptococcus spp. is an invasive fungal pathogen and causes life-threatening cryptococcosis. Opportunistic cryptococcal infections among the immunocompromised population are mostly caused by Cryptococcus neoformans, whereas the geographical dissemination of Cryptococcus gattii in recent years has threatened lives of even immunocompetent people. The capsule, mainly composed of glucuronoxylomannan (GXM) polysaccharides, plays important roles in the virulence of Cryptococcus spp. The assembling mechanism of GXM polysaccharides into the capsule is little understood because of insufficient experimental data. Molecular modeling and molecular dynamics simulation provide insight into the assembling process. We first built GXM oligosaccharide models of serotypes D, A, B, and C and extracted their secondary structure information from simulation trajectories. All the four mainchains tend to take the nearly twofold helical conformation, whereas peripheral sidechains prefer to form left-handed helices, which are further stabilized by intramolecular hydrogen bonds. Based on the obtained secondary structure information, GXM polysaccharide arrays were built to simulate capsule-assembling processes of C. neoformans and C. gattii using serotypes A and C as representatives, respectively. Trajectory analysis illustrates that electrostatic neutralization of acidic sidechain residues of GXM is a prerequisite for capsule assembling, followed by formation of intermolecular hydrogen bond networks. Further insight into the assembling mechanism of GXM polysaccharides provides the possibility to develop novel treatment and prevention solutions for cryptococcosis.

Insight of Transmembrane Processes of Self-Assembling Nanotubes Based on a Cyclic Peptide Using Coarse Grained Molecular Dynamics Simulation.

Transmembrane self-assembling cyclic peptide (SCP) nanotubes are promising candidates for delivering specific molecules through cell membranes. The detailed mechanisms behind the transmembrane processes, as well as stabilization factors of transmembrane structures, are difficult to elucidate through experiments. In this study, the effects of peptide sequence and oligomeric state on the transmembrane capabilities of SCP nanotubes and the perturbation of embedded SCP nanotubes acting on the membrane were investigated based on coarse grained molecular dynamics simulation. The simulation results reveal that hydrophilic SCP oligomers result in the elevation of the energy barrier while the oligomerization of hydrophobic SCPs causes the reduction of the energy barrier, further leading to membrane insertion. Once SCP nanotubes are embedded, membrane properties such as density, thickness, ordering state and lateral mobility are adjusted along the radial direction. This study provides insight into the transmembrane strategy of SCP nanotubes and sheds light on designing novel transport systems.

Rapid delivery of paclitaxel with an organic solvent-free system based on a novel cell penetrating peptide for suppression of tumor growth.

Paclitaxel (PTX) is widely used to treat ovarian, breast, lung, pancreatic, cervical and other cancers, however, the cell uptake and utilization of PTX is greatly limited by its slow penetration rate and poor solubility in water. Therefore, it is of great interest to develop an efficient method for PTX delivery to improve its cellular uptake and utilization. A novel cell penetrating peptide, RRRRRWW (R7), is developed to accelerate the translocation of PTX into HeLa cells in the organic solvent-free system to suppress tumor growth. There is no significant cytotoxicity induced by the peptide alone even after 24 h incubation at 1 mM at 37 °C for both cancer cells and normal cells. In contrast, 30 min treatment with the R7/PTX complex leads to a significant decrease in the cell viability. The intracellular PTX concentration of the R7/PTX complex group is 3 fold that of the free PTX group. The in vivo animal experiments show that the tumor is dramatically suppressed by a tail vein injection of the R7/PTX complex. This system provides a novel approach for the delivery of PTX into tumor cells to efficiently suppress tumor growth.