Expanding the world of protein secondary structure beyond boundaries of evolution

点击翻译按钮获取中文摘要

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.