Barrera Exequiel E, Zonta Francesco, Pantano Sergio
Instituto de Histología y Embriología (IHEM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), CC56, Universidad Nacional de Cuyo (UNCuyo), Mendoza, Argentina.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
Comput Struct Biotechnol J. 2021 Mar 13;19:1595-1602. doi: 10.1016/j.csbj.2021.02.014. eCollection 2021.
Poly glutamine and glutamine-rich peptides play a central role in a plethora of pathological aggregation events. However, biophysical characterization of soluble oligomers -the most toxic species involved in these processes- remains elusive due to their structural heterogeneity and dynamical nature. Here, we exploit the high spatio-temporal resolution of coarse-grained simulations as a computational microscope to characterize the aggregation propensity and morphology of a series of polyglutamine and glutamine-rich peptides. Comparative analysis of ab-initio aggregation pinpointed a double role for glutamines. In the first phase, glutamines mediate seeding by pairing monomeric peptides, which serve as primers for higher-order nucleation. According to the glutamine content, these low molecular-weight oligomers may then proceed to create larger aggregates. Once within the aggregates, buried glutamines continue to play a role in their maturation by optimizing solvent-protected hydrogen bonds networks.
聚谷氨酰胺和富含谷氨酰胺的肽在众多病理性聚集事件中起着核心作用。然而，可溶性寡聚体是这些过程中最具毒性的物种，由于其结构异质性和动态性质，对其进行生物物理表征仍然很困难。在这里，我们利用粗粒度模拟的高时空分辨率作为一种计算显微镜，来表征一系列聚谷氨酰胺和富含谷氨酰胺的肽的聚集倾向和形态。从头算聚集的比较分析指出了谷氨酰胺的双重作用。在第一阶段，谷氨酰胺通过配对单体肽来介导成核，这些单体肽作为高阶成核的引物。根据谷氨酰胺含量，这些低分子量寡聚体随后可能会形成更大的聚集体。一旦进入聚集体，埋藏的谷氨酰胺通过优化溶剂保护的氢键网络继续在其成熟过程中发挥作用。
