Computational design of self-assembling cyclic protein homo-oligomers.
Computational design of self-assembling cyclic protein homo-oligomers.
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DOI：
10.1038/nchem.2673
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发表时间：
2017-04
期刊：
影响因子：
21.8
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Fallas JA;Ueda G;Sheffler W;Nguyen V;McNamara DE;Sankaran B;Pereira JH;Parmeggiani F;Brunette TJ;Cascio D;Yeates TR;Zwart P;Baker D
自组装环状蛋白同源寡聚体在生物学中起着重要作用，并且产生定制同源寡聚体结构的能力可以使新的方法能够探测生物功能。在这里，我们报告了一种通用的方法来设计环状同源寡聚体，采用一种新的残基对转换方法评估蛋白质-蛋白质界面的设计能力。这种方法是足够快，使系统枚举的循环对接安排的单体，然后由新形成的接口的序列设计。我们使用这种方法来设计接口到理想化的重复蛋白质，直接组装成具有循环对称性的复合物。在96个实验表征的设计中，发现21个在溶液中形成稳定的单分散均聚物，并且15个（4个均二聚物，6个均三聚物，6个均四聚物和1个均五聚物）具有与设计模型一致的溶液小角X射线散射数据。获得了五种设计的X射线晶体结构，并且每一种都显示出非常接近其设计模型。
Self-assembling cyclic protein homo-oligomers play important roles in biology and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homo-oligomers that employs a new residue pair transform method for assessing the design ability of a protein-protein interface. This method is sufficiently rapid to enable systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were experimentally characterized, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (4 homodimers, 6 homotrimers, 6 homotetramers and 1 homopentamer) had solution small angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each of these were shown to be very close to their design model.