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

spp. is an invasive fungal pathogen and causes life-threatening cryptococcosis. Opportunistic cryptococcal infections among the immunocompromised population are mostly caused by , whereas the geographical dissemination of 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 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 and 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.