正交蛋白异构体的可编程设计
Zibo Chen1,2,3, Scott E Boyken1,2, Mengxuan Jia4
1Department of Biochemistry, University of Washington, Seattle, WA, USA.
Nature
|December 21, 2018
概括
科学家使用键设计了具有高特异性的新型蛋白质异构体. 这一突破为合成生物学应用提供了先进的控制逻辑.
科学领域:
- 生物化学
- 结构生物学
- 合成生物学
背景情况:
- 蛋白与蛋白相互作用的特异性通常依赖于脊柱形状的互补性,这是很难概括的.
- 现有的方法,如卷轴型异构体,对于创建直角对的模块性有限.
- 实现特定的蛋白质相互作用通常涉及模块化侧链变异,与DNA或蛋白质-DNA相互作用不同.
研究的目的:
- 通过广泛和模块化的侧链键网络来证明蛋白与蛋白相互作用的特异性.
- 通过计算设计和实验验证具有高特异性和正交度的新型蛋白质异构体.
- 在合成生物学中探索可编程生物分子相互作用的新可能性.
主要方法:
- 使用克里克生成方程创建多个四螺旋脊柱与受控的超级卷.
- 采用Rosetta软件进行循环设计和序列优化以形成异构体.
- 在大肠杆菌中表达和特征设计的蛋白质,包括通过X射线结晶学进行结构分析和使用原生质谱的相互作用分析.
主要成果:
- 成功设计了97个蛋白质异构体,其中65个在表达时形成构成性异构体.
- 四个设计的晶体结构证实了计算模型和设计的键网络的存在.
- 在细胞环境 (六个完全直角异构体) 和体外环境中显示出高直角性,设计对在变性和重新化后显示出优先结合.
结论:
- 广泛和模块化的侧链键网络可以为蛋白质-蛋白质相互作用提供高特异性.
- 开发的计算和实验方法可以设计正交的蛋白质异构体.
- 这种能力为合成生物学中基于蛋白质的复杂控制逻辑开辟了道路,扩大了可编程生物分子相互作用的范围.
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