蛋白质-蛋白质接口的组合限制计算设计,以产生IgG异构体
Tala Azzam1, Jonathan J Du1, Maria W Flowers1
1Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Science advances
|April 10, 2024
概括
我们开发了 combYSelect,一种使用氨酸和氨酸的计算方法,用于重新设计用于治疗的蛋白质接口. 这种方法有效地产生稳定,功能性免疫球蛋白G (IgG) 异构体,用于像双特异性抗体这样的应用.
科学领域:
- 生物化学 生化学
- 计算生物学 计算生物学
- 结构生物学 结构生物学
背景情况:
- 蛋白质-蛋白质接口重新设计对于开发新疗法至关重要.
- 在 silico 选提供了蛋白质变体的有效采样,但面临着计算限制.
- 目前的方法努力平衡计算成本与蛋白质序列空间的广.
研究的目的:
- 介绍组合式氨酸 (Y) /氨酸 (S) 选择 (combYSelect),一种用于蛋白质接口重新设计的新型计算方法.
- 使用 combYSelect 方法设计和验证免疫球蛋白 G (IgG) 异构体.
- 为了证明工程异构体的治疗适用性.
主要方法:
- 开发了combYSelect,集成在结的自由能量变化 (ΔΔG) 计算与受限制的氨酸和氨酸残留物库.
- 应用CombYSelect来设计两个IgG异构体:CombYSelect1和CombYSelect2.
- 确定工程异构体的晶体结构,以分析相互作用机制.
主要成果:
- 成功设计了两个IgG异构体 (combYSelect1和combYSelect2),具有接近最佳的异构体化.
- 证实工程异构体保持了IgG的稳定性和功能.
- 确定了动态 π 堆叠和极性接触作为偏好的异构体相互作用的关键驱动因素.
- 设计了一种双特异性抗体和一个细胞因子陷,使用设计的异构体用于治疗应用.
结论:
- combYSelect是一种有效的计算策略,用于设计稳定和功能性的蛋白质异构体.
- 工程化异构体作为开发先进生物制剂的多功能平台,包括双特异性抗体和细胞因子陷.
- 这种方法通过克服计算成本限制,显著推进了蛋白质工程领域的治疗开发.
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