Fu Yankai, Huang Xinglu, Zhou Zeqi
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
Beijing Key Laboratory for Mechanism Study and Precision Diagnosis of Invasive Fungal Diseases, Dynamiker Biotechnology Sub-Center, Tianjin 300467, China.
ACS Omega. 2020 Nov 3;5(45):29351-29356. doi: 10.1021/acsomega.0c04164. eCollection 2020 Nov 17.
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.
新型隐球菌是一种侵袭性真菌病原体，可导致危及生命的隐球菌病。免疫功能低下人群中的机会性隐球菌感染主要由新型隐球菌引起，而近年来新型隐球菌的地理传播甚至威胁到了免疫功能正常人群的生命。荚膜主要由葡糖醛酸木甘露聚糖（GXM）多糖组成，在新型隐球菌的毒力中起重要作用。由于实验数据不足，GXM多糖组装成荚膜的机制尚不清楚。分子建模和分子动力学模拟为组装过程提供了见解。我们首先构建了血清型D、A、B和C的GXM寡糖模型，并从模拟轨迹中提取了它们的二级结构信息。所有四条主链都倾向于采取近两倍的螺旋构象，而外围侧链则倾向于形成左手螺旋，这些螺旋通过分子内氢键进一步稳定。基于获得的二级结构信息，构建了GXM多糖阵列，分别以血清型A和C为代表模拟新型隐球菌和格特隐球菌的荚膜组装过程。轨迹分析表明，GXM酸性侧链残基的静电中和是荚膜组装的先决条件，随后形成分子间氢键网络。对GXM多糖组装机制的进一步深入了解为开发新型隐球菌病的治疗和预防方案提供了可能性。
