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首页> 外文期刊>Journal of Molecular Biology >Computational redesign of a protein-protein interface for high affinity and binding specificity using modular architecture and naturally occurring template fragments.
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Computational redesign of a protein-protein interface for high affinity and binding specificity using modular architecture and naturally occurring template fragments.

机译：使用模块化结构和天然模板片段进行蛋白质-蛋白质界面的计算重新设计，以实现高亲和力和结合特异性。

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摘要

A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 beta-lactamase and its inhibitor protein, beta-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 10(7) starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.
机译：提出了一种重新设计蛋白质-蛋白质界面的新方法，该方法可在保持高亲和力的同时提高设计对的特异性。该设计基于模块化接口体系结构，并且是基于TEM1β-内酰胺酶与其抑制剂蛋白β-内酰胺酶抑制剂蛋白之间的相互作用进行的。这两种蛋白质之间的界面由几个大部分独立的模块组成。之前，我们表明可以删除一个完整的模块而不会影响接口的整体结构。在这里，我们用取自无关蛋白的结构片段代替了完整的模块。从Protein Data Bank中找到的10（7）个起始模板中选择经过自然优化的片段。然后开发了一种程序，以识别具有模仿原始模块的骨架结构的相互作用模板残基集。这生成了361个推定替换模块的最终列表，这些模块使用基于分组的原子-原子接触表面积的新颖评分功能进行了排名。尽管该程序中没有阴性设计，但排名最高的设计复合物表现出至少野生型水平的亲和力和非常特异性的结合方式。回顾过去，三个因素的综合应用导致了设计方法的成功：利用界面的模块化构造，利用本机而非人工模板，并利用精确的原子-原子接触表面评分功能进行排名。

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