Computational design of specific binding proteins using Leave-One-Out

描述(申请人提供)：使用留一法设计特定结合蛋白的计算机设计这项研究的目标是能够为任何蛋白质靶标设计一种受体蛋白。此外，我们认为结合事件将通过酶活性或荧光的出现来发出信号。这种新的结合蛋白将能够感知和报告特定蛋白质或肽在其他混合物中的存在，从而能够在体内和体外检测疾病病原体或其他感兴趣的蛋白质。这一新方法利用了蛋白质折叠途径。当蛋白质折叠时，它们以特定的事件顺序进行，可以根据蛋白质的结构预测事件。当蛋白质完成折叠时，它的活性就会立即启动。如果我们遗漏了一小段蛋白质，导致折叠无法完成，那么蛋白质就会处于不活跃状态，直到缺失的那一段出现。使用这种留下一个的策略，部分折叠的蛋白质成为它们缺失片段的传感器。利用计算机设计算法，一个新的氨基酸序列可以取代遗漏的片段。这个新的序列可以来自炭疽、禽流感、癌细胞标记物或任何其他蛋白质。使用大规模并行计算集群和网格计算，并根据蛋白质折叠和能量计算的已知知识，将设计任务划分为许多较小的任务，从而实现了对这一新序列周围氨基酸的计算替代。最终的设计是一种包裹在目标多肽周围的蛋白质，通过其互补的形状专门识别它。绿色荧光蛋白一直是第一个Leave-One-Out设计研究的对象，它产生了只有在靶标多肽存在时才发光的特定结合蛋白。

DESCRIPTION (provided by applicant): Computational design of specific binding proteins using Leave-One-Out The goal of this research is to be able to design a receptor protein for any protein target. Furthermore, we propose that the binding event will be signaled by the appearance of enzyme activity or fluorescence. The novel binding proteins will be able to sense and report the presence of a specific protein or peptide in a mixture of others, allowing the detection of disease agents or other proteins of interest both in vivo and in vitro. The new approach takes advantage of protein folding pathways. When proteins fold, they do so in a specified order of events, and the events can be predicted based on the structure of the protein. When a protein finishes folding, its activity is immediately turned on. If we leave out one small piece of the protein so that the folding cannot finish, then the protein sits in an inactive state ntil the missing piece appears. Using this Leave-One- Out strategy, partially folded proteins become sensors for their missing pieces. Using computational design algorithms, a new amino acid sequence can be substituted for the left out piece. This new sequence can be from anthrax, avian flu, a cancer cell marker or any other protein. Computational substitution of the amino acids surrounding this new sequence is made possible using massively parallel computing clusters and grid computing, and by dividing the design task into numerous smaller tasks based on what is known about protein folding and energy calculations. The final design is a protein that wraps around the target peptide, specifically identifying it by its complementary shape. Green fluorescent protein has been the subject of the first leave-one-out design studies and has yielded specific binding proteins that glow only when the target peptide is present.