Expanding the world of protein secondary structure beyond boundaries of evolution

对于一个平均大小的蛋白质来说，只有极小的氨基酸序列曾经被自然进化过程所采样。做出微小改变并根据结果进行选择的过程意味着蛋白质被聚集到序列和结构相似的微小孤岛中。绝大多数的蛋白质设计努力也同样受到限制，只是逐渐远离已经存在的东西。即使是目前在从头蛋白质设计方面的努力，在探索与自然截然不同的序列的同时，也坚持相同的基本二级结构。我们提出了一个跳入未采样蛋白质空间的浩瀚海洋的研究计划。到目前为止，这一领域的工作主要是寻找从头开始的序列，这些序列将形成常见的二级结构，如α螺旋和β-折叠。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。我们将不再专注于序列，而是探索肽骨架与自身相互作用的复杂方式。然后，我们将测试哪些序列稳定了这些结构，并探索了可能导致这些结构的折叠途径。所有这些都将在体外测试我们的结构并产生三维结构之前通过计算完成。我们预计，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.