An Interface-Driven Design Strategy Yields a Novel, Corrugated Protein Architecture
An Interface-Driven Design Strategy Yields a Novel, Corrugated Protein Architecture
复制标题
DOI：
10.1021/acssynbio.8b00224
复制
发表时间：
2018-09-01
影响因子：
4.7
通讯作者：
Lupas, Andrei N.
中科院分区：
文献类型：
--
作者：
ElGamacy, Mohammad;Coles, Murray;Lupas, Andrei N.
使用新颖的褶皱设计蛋白质仍然是一个重大挑战，因为目标折叠的生物物理特性尚不清楚，并且没有序列曲线来描述其特征。因此，到目前为止，大多数计算设计工作都是针对创建概括现有折叠的蛋白质的。在这里，我们提出了一种以新型分子内接口设计为中心的策略，该策略可以从一组起始片段中构造目标折叠。该策略有效地减少了实现最佳序列所需的计算采样量，而不会损害拓扑控制水平。螺线管结构一直是广泛的蛋白质设计工作的目标，因为它提供了一个高度模块化的拓扑复杂性平台。但是，以前的努力都没有试图偏离自然形式，而自然形式的特征是统一的超螺旋体系结构。在这里，我们旨在设计一个更复杂的平台，通过引入内部交替的握手来消除超前，从而导致了一种新颖的波纹体系结构。我们采用了接口驱动的策略，设计了三种蛋白质，并通过解决两个示例的结构来确认设计。
Designing proteins with novel folds remains a major challenge, as the biophysical properties of the target fold are not known a priori and no sequence profile exists to describe its features. Therefore, most computational design efforts so far have been directed toward creating proteins that recapitulate existing folds. Here we present a strategy centered upon the design of novel intramolecular interfaces that enables the construction of a target fold from a set of starting fragments. This strategy effectively reduces the amount of computational sampling necessary to achieve an optimal sequence, without compromising the level of topological control. The solenoid architecture has been a target of extensive protein design efforts, as it provides a highly modular platform of low topological complexity. However, none of the previous efforts have attempted to depart from the natural form, which is characterized by a uniformly handed superhelical architecture. Here we aimed to design a more complex platform, abolishing the superhelicity by introducing internally alternating handedness, resulting in a novel, corrugated architecture. We employed our interface-driven strategy, designing three proteins and confirming the design by solving the structure of two examples.