Expanding the world of protein secondary structure beyond boundaries of evolution

对于一个平均大小的蛋白质，只有一个极小的氨基酸序列子集被自然进化过程采样过。根据产生的效果进行微小改变和选择的过程意味着蛋白质聚集成序列和结构相似的微小岛屿。绝大多数的蛋白质设计努力都受到类似的限制，只能逐步远离已经存在的东西。即使是目前在从头开始的蛋白质设计中所做的努力，在探索与自然截然不同的序列时，也坚持使用相同的基本二级结构。我们提出了一项研究计划，该计划将跨入未采样蛋白质空间的浩瀚海洋。到目前为止，这一领域的工作一直是为了寻找新的序列，这些序列将形成常见的二级结构，如-螺旋和-薄片。我们有一种不同的方法，即假设存在其他更奇特的二级结构。而不是集中在序列，我们将探索肽主链可以相互作用的复杂方式。然后，我们将测试哪些序列稳定这些结构，并探索可能导致它们的折叠途径。所有这些都将在计算中完成，然后在体外测试我们的结构，并生成三维结构。我们期待发现新的蛋白质二级结构将开辟合成生物学的新前沿。

For an average size protein, only an infinitesimal subset of amino acid sequences have ever been sampled by natural evolutionary processes. The process of making small changes and selecting based on the resulting effect means that proteins are clustered into tiny islands of sequence and structure similarity. The vast majority of protein design endeavours are similarly constrained and only step incrementally away from what already exists. Even the current efforts in de novo protein design, while exploring very different sequences to nature, stick to the same basic secondary structures. We propose a program of research that leaps into the vast ocean of unsampled protein space. Up to now, work in this field has been directed toward finding de novo sequences that will form commonly seen secondary structures, such as alpha helices and beta-sheets. We have a different approach, namely hypothesizing that other, more exotic secondary structures exist. Instead of concentrating on sequence, we will explore complex ways in which peptide backbone can interact with itself. We will then test which sequences stabilize these structures, and explore the folding pathways that might lead to them. All of this will be done computationally, before testing our structures in vitro, and generating three-dimensional structures. We anticipate that finding new protein secondary structures will open up a new frontier in synthetic biology.