Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Fu Y

PROVIDER: S-EPMC7676341 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Fu Yankai Y Huang Xinglu X Zhou Zeqi Z

ACS omega 20201103 45

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 ...[more]

PMID: 33225166

Similar Datasets

Project description:Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer's disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer's disease with a potentially wider therapeutic window and fewer adverse side effects.

Dataset Information

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

Publications

Insight into the Assembling Mechanism of <i>Cryptococcus</i> Capsular Glucuronoxylomannan Based on Molecular Dynamics Simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets