Harbury P B, Plecs J J, Tidor B, Alber T, Kim P S
Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
Science. 1998 Nov 20;282(5393):1462-7. doi: 10.1126/science.282.5393.1462.
Recent advances in computational techniques have allowed the design of precise side-chain packing in proteins with predetermined, naturally occurring backbone structures. Because these methods do not model protein main-chain flexibility, they lack the breadth to explore novel backbone conformations. Here the de novo design of a family of alpha-helical bundle proteins with a right-handed superhelical twist is described. In the design, the overall protein fold was specified by hydrophobic-polar residue patterning, whereas the bundle oligomerization state, detailed main-chain conformation, and interior side-chain rotamers were engineered by computational enumerations of packing in alternate backbone structures. Main-chain flexibility was incorporated through an algebraic parameterization of the backbone. The designed peptides form alpha-helical dimers, trimers, and tetramers in accord with the design goals. The crystal structure of the tetramer matches the designed structure in atomic detail.
计算技术的最新进展使得能够在具有预定天然存在的主链结构的蛋白质中设计精确的侧链堆积。由于这些方法没有对蛋白质主链的灵活性进行建模，它们缺乏探索新型主链构象的广度。本文描述了一族具有右手超螺旋扭曲的α-螺旋束蛋白的从头设计。在设计中，整体蛋白质折叠由疏水-极性残基模式指定，而束寡聚化状态、详细的主链构象和内部侧链旋转异构体则通过在交替主链结构中的堆积计算枚举来设计。通过主链的代数参数化纳入了主链灵活性。所设计的肽符合设计目标形成α-螺旋二聚体、三聚体和四聚体。四聚体的晶体结构在原子细节上与设计结构匹配。
