Computational design of a protein crystal
Computational design of a protein crystal
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DOI：
10.1073/pnas.1112595109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Saven, Jeffery G.
中科院分区：
文献类型：
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作者：
Lanci, Christopher J.;MacDermaid, Christopher M.;Saven, Jeffery G.
蛋白质晶体具有催化和材料应用，是结构生物学和治疗发展的核心。考虑到蛋白质的复杂性和控制结晶的非共价相互作用，设计预先确定的晶体结构可能是微妙的。从头开始的蛋白质设计提供了一种设计高度复杂的纳米级分子结构的方法，并且通常可以以亚埃精度编程原子的位置。本文提出了一种计算方法，用于设计三维自组装以产生宏观晶体的蛋白质。一种三螺旋螺旋蛋白被重新设计成具有P6空间基团的极性、分层、三维晶体，具有“蜂窝状”结构和跨越晶体的六聚体通道。该方法包括：(i)创建与目标对称一致的晶体结构集合；（ii）从序列-结构能量景观的最小值中识别出“可设计”的结构，并为这些结构设计序列；（iii）实验表征候选蛋白。一个这样设计的蛋白质的2.1埃分辨率x射线晶体结构与晶体的计算模型显示出亚埃一致性[主干均方根偏差（rmsd）]。这种晶体设计方法在纳米结构材料的从头设计和天然蛋白质的修饰以促进x射线晶体学分析方面具有潜在的应用前景。
Protein crystals have catalytic and materials applications and are central to efforts in structural biology and therapeutic development. Designing predetermined crystal structures can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallization. De novo protein design provides an approach to engineer highly complex nanoscale molecular structures, and often the positions of atoms can be programmed with sub-angstrom precision. Herein, a computational approach is presented for the design of proteins that self-assemble in three dimensions to yield macroscopic crystals. A three-helix coiled-coil protein is designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which has a "honeycomb-like" structure and hexameric channels that span the crystal. The approach involves: (i) creating an ensemble of crystalline structures consistent with the targeted symmetry; (ii) characterizing this ensemble to identify "designable" structures from minima in the sequence-structure energy landscape and designing sequences for these structures; (iii) experimentally characterizing candidate proteins. A 2.1 angstrom resolution X-ray crystal structure of one such designed protein exhibits sub-angstrom agreement [backbone root mean square deviation (rmsd)] with the computational model of the crystal. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.