在交叉反应性抗体设计中观察局部形状动态的再分配
Yoshiki Yasuda1, Satoru Nagatoishi2, Jiei Sasaki3
1Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Journal of biochemistry
|March 11, 2026
概括
抗体工程可能具有挑战性. 对SARS-CoV-1抗体 (m396) 的计算重新设计使SARS-CoV-2的识别成为可能,揭示了突变如何改变动态和交叉反应.
科学领域:
- 免疫学 免疫学 免疫学
- 结构生物学 结构生物学
- 计算生物学 计算生物学
背景情况:
- 抗体工程通常依赖于广泛的突变发生和查.
- 增强抗体交叉反应性的突变的生物物理基础尚未得到充分理解.
研究的目的:
- 通过计算重新设计SARS-CoV-1中和抗体m396以结合SARS-CoV-2受体结合域 (RBD).
- 描述工程抗体变体的生物物理性质,阐明改变交叉识别的机制.
主要方法:
- 计算式蛋白质重新设计.
- 局部导向的突变发生.
- 生物物理特征 (循环二元化,差分扫描热量计)
- -交换质谱法 (HDX-MS) 是一种质谱法.
主要成果:
- 一个具有三个轻链替代的第一代变体获得了SARS-CoV-2 RBD结合,同时保持了SARS-CoV RBD亲和力.
- 一种具有两种替代的第二代变异实现了对SARS-CoV-2 RBD的低微分子亲和力,由增加的关联率驱动.
- 生物物理分析表明,全球折叠保持,但局部动态发生变化,包括增加CDR-L1的灵活性和CDR-H2的刚性.
结论:
- 少数突变可以通过调节局部形状动态来重新编程抗体交叉识别.
- 这项研究提供了一个生物物理模型,用于理解和设计抗体交叉反应.
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