Expanding the world of protein secondary structure beyond boundaries of evolution

扩展蛋白质二级结构的世界，超越进化的界限

• 批准号: RGPIN-2020-06855
• 负责人: Garton, Michael
• 金额: $ 2.19万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741384
• 关键词: Expanding; world; protein; secondary; structure

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.

对于一个平均大小的蛋白质，只有一个无限小的氨基酸序列子集曾经被自然进化过程所采样。进行微小的改变并根据产生的效果进行选择的过程意味着蛋白质被聚集成序列和结构相似的小岛。绝大多数蛋白质设计工作都受到类似的限制，只能逐步远离已经存在的东西。即使是目前在从头设计蛋白质方面的努力，虽然探索了与自然界非常不同的序列，但仍然坚持相同的基本二级结构。我们提出了一个研究计划，跳入未采样蛋白质空间的汪洋大海。到目前为止，该领域的工作一直致力于寻找将形成常见二级结构的从头序列，如α螺旋和β折叠。我们有一个不同的方法，即假设存在其他更奇特的二级结构。我们将探索肽骨架与自身相互作用的复杂方式，而不是集中在序列上。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。所有这些都将在体外测试我们的结构并生成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。