原模仿二元化的自由能量和对纤维化的影响
George A Pantelopulos1, Ayan Majumder2, John E Straub2
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
Biophysical journal
|January 15, 2026
概括
原三螺旋组装是复杂的. 分子动力学模拟揭示了不同的二分化模式,其中"充电拉链"序列促进了比Proline-Hydroxyproline-Glycine重复形成纤维的更强的关联.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 生物物理学的生物物理.
背景情况:
- 原纤维对细胞外矩阵结构和功能至关重要.
- 控制原纤维组合的分子机制尚未完全理解.
- 原三螺旋体的大小和异质性对表征提出了挑战.
研究的目的:
- 用分子动力学 (MD) 模拟来研究模型原仿真三重螺旋体的二元化自由能量景观.
- 在生理条件下,描述原三重螺旋之间的不同协作模式.
- 了解序列图案如何影响原三环二元化和潜在纤维细胞的形成.
主要方法:
- 用分子动力学 (MD) 模拟来建模原仿真三重螺旋体.
- 对不同的序列计算了二元化自由能量场景.
- 分析的重点是疏水相互作用,结合 (包括Hydroxyproline-Hydroxyproline) 和盐桥形成.
主要成果:
- 氨酸-氨酸-甘氨酸 (POG) 重复域通过疏水性关联和氨酸 (Hyp) 键容易二元化.
- 具有稳定螺旋内盐桥的异构三环螺旋体,由于受阻相互作用,显示出较弱的关联.
- 一个设计的"充电拉链"序列促进了更强大的螺旋间盐桥,导致二极管比POG重复二极管稳定两倍多.
- 纤维状原体中约有25%的充电残留物参与了螺旋内部的盐桥,限制了它们在螺旋间相互作用的可用性.
结论:
- 存在多种,主要是正交的,原三环联结的模式.
- 序列设计,特别是涉及带电残留物和特定图案,如"充电拉链",显著影响螺旋体二分化.
- 螺旋内部的盐桥可以通过隔离带电残留物来阻碍纤维的形成,这表明电荷在原组合中的作用比以前假设的更为细微.
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