The functional sites of many protein families are dominated by diverse backbone regions that lack secondary structure (loops) but fold stably into their functionally competent state. Nevertheless, the design of structured loop regions from scratch, especially in functional sites, has met with great difficulty. We therefore developed an approach, called AbDesign, to exploit the natural modularity of many protein families and computationally assemble a large number of new backbones by combining naturally occurring modular fragments. This strategy yielded large, atomically accurate, and highly efficient proteins, including antibodies and enzymes exhibiting dozens of mutations from any natural protein. The combinatorial backbone‐conformation space that can be accessed by AbDesign even for a modestly sized family of homologs may exceed the diversity in the entire PDB, providing the sub‐Ångstrom level of control over the positioning of active‐site groups that is necessary for obtaining highly active proteins. This manuscript describes how to implement the pipeline using code that is freely available at https://github.com/Fleishman‐Lab/AbDesign_for_enzymes.

中文翻译：

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用于模块化骨架组装以及粘合剂和酶设计的AbDesign计算管道

许多蛋白质家族的功能位点由缺乏二级结构（环）但稳定折叠成其功能能力状态的不同骨架区域控制。然而，特别是在功能站点中，从头开始设计结构化环区域遇到了很大的困难。因此，我们开发了一种名为AbDesign的方法，以利用许多蛋白质家族的天然模块性，并通过结合天然存在的模块片段，以计算机方式组装大量新的骨架。这种策略产生了大的，原子上精确的高效蛋白质，包括抗体和酶，这些蛋白质和酶显示出任何天然蛋白质都有数十种突变。AbDesign可以访问的组合主干构型空间即使对于中等规模的同系物家族，也可能超出整个PDB的多样性，从而提供了对获得高活性蛋白质所必需的活性位点组定位的亚埃级控制。该手稿描述了如何使用https://github.com/Fleishman‐Lab/AbDesign_for_enzymes上免费提供的代码来实现管道。