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通过点选择,设计一种治疗综合体的机械稳定性,该综合体位于附属体和被编程死亡体1之间

Byeongseon Yang^1,2, Diego E B Gomes³, Zhaowei Liu^1,2

¹Institute for Physical Chemistry, Department of Chemistry, University of Basel, 4058 Basel, Switzerland.

|November 8, 2024

概括

机械力方向显著影响蛋白质复合体的稳定性. 优化Affibody和编程死亡连接体1 (PD-L1) 上的生物结合部位增强了复杂的机制稳定性,这对于药物输送至关重要.

科学领域:

生物物理学的生物物理.
分子机械生物学分子机械生物学
蛋白质工程是指蛋白质的工程.

背景情况:

蛋白质-蛋白质复合体的机械稳定性取决于方向.
了解这种机械稳定性对于药物输送等应用来说至关重要.

研究的目的:

调查依赖于力方向的机械稳定性Affibody:编程死亡-Ligand 1 (PD-L1) 复合体.
确定特定地点的生物结合如何影响复杂的机械稳定性.

主要方法:

原子力显微镜 (AFM) 单分子力光谱学.
生物对角可点击柄.生物对角可点击柄.
剪切应力珠粘附测试. 剪切应力珠粘附测试.
分子建模和定向分子动力学 (SMD).

主要成果:

破裂力根据拉动点而有显著的变化.
与N端拉力相比,从特定的Affibody残留物 (例如, #22, #47) 拉出会产生更高的破裂力 (高达~190 pN).
从N端拉动导致了强力激活的捕获键,而从残留物#22拉动诱导了PD-L1展开的中间状态.
SMD模拟证实了实验结果,并提供了对力传播的机械洞察力.

结论:

蛋白质-蛋白质接口的机械性质可以通过特定位置的生物结合来调整.
根据对结合部位的知情选择可以优化蛋白质复合物的机械稳定性.
这些发现对设计药物输送系统中有效的生物结合策略有影响.

关键词:

原子力显微镜的原子力显微镜.生物物理学的生物物理学.固定化固定化固定化分子动力学分子动力学分子识别分子识别蛋白质工程工程蛋白质工程

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