Intruding into the midnight zone of protein comparisons

闯入蛋白质比较的午夜区域

• 批准号: 6520482
• 负责人: BURKHARD ROST
• 金额: $ 28.02万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-05 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520482
• 关键词: DNA binding protein; automated data processing; binding sites; biochemical evolution; chemical chain length; computer simulation; computer system design /evaluation; conformation; data management; functional /structural genomics; membrane proteins; molecular biology information system; molecular dynamics; protein sequence; protein structure function; proteomics; statistics /biometry; structural biology

Description (provided by applicant): The 'twilight zone' of protein sequence comparison is the region in which sequence similarity does not suffice to conclude e.g. structural similarity. The vast majority of all protein pairs of similar structure populate a 'midnight zone' i.e. their sequences differ too much for sequence-based comparisons. Here, we propose to refine, extend, and specialise methods combining sequence alignment, structure prediction and functional information. Goal is to unravel hidden similarities in entirely sequenced organisms by a reliable, automatic tool. Towards the end of our project, the sequences for most protein families realised by life will supposedly be available. We hope that our system will correctly detect a relation for most of these. (1) Prediction-based threading combines sequence alignments with predictions of secondary structure and accessibility to find remote similarities. We hope to considerably improve detection and alignment accuracy by comparing families with families rather than single proteins. (2) About one third of all proteins in worm and fly seem to have long regions lacking regular secondary structure. We hope to develop a method tailored to reliably detect and compare such regions. (3) No current method finds similarities between extremely diverged membrane proteins. We propose to develop such a method combining 'membrane threading' with classifications of membrane proteins. (4) Since sequence comparison in the twilight zone and below is an extremely demanding task, most existing methods have very low levels of accuracy. In practice, experts compare aspects of function between the protein pair under investigation. We want to develop an automatic method evaluating functional aspects. In particular, we intend to start with proteins binding to DNA. The tasks will be to (i) predict DNA-binding sites in proteins, and to (ii) restrict the threading to the subset of proteins for which binding regions were found. In the following step, we hope to use general sequence motifs for the automatic comparison. (5) Threading entire genomes: the first task will be to find all proteins in an entire organism for which we know structure. However, the particular edge of our method will be to find remote similarities even in the absence of experimental information about structure.

描述（由申请人提供）：蛋白质序列的“暮光区” 比较是序列相似性不足以判断的区域 总结例如结构相似性。所有蛋白质对中的绝大多数 类似的结构填充了“午夜区域”，即它们的序列也不同 非常适合基于序列的比较。在此，我们建议完善、扩展和 结合序列比对、结构预测和 功能信息。目标是完全揭示隐藏的相似之处 通过可靠的自动工具对生物体进行测序。在我们的即将结束时 项目中，生命实现的大多数蛋白质家族的序列将 据说可以使用。我们希望我们的系统能够正确检测到 其中大多数的关系。 (1) 基于预测的线程将序列比对与预测相结合 二级结构和可访问性以找到远程相似性。我们希望 通过比较族显着提高检测和对准精度 与家族而不是单一蛋白质。 (2) 约三分之一的蛋白质 蠕虫和苍蝇似乎具有缺乏规则二级结构的长区域。 我们希望开发一种方法来可靠地检测和比较此类 地区。 (3) 目前没有方法发现极端分歧之间的相似之处 膜蛋白。我们建议开发一种结合“膜”的方法 线程'与膜蛋白的分类。 (4) 自序列 在暮光区及以下区域进行比较是一项极其艰巨的任务，大多数 现有方法的准确度非常低。专家在实践中比较 正在研究的蛋白质对之间的功能方面。我们想要 开发一种评估功能方面的自动方法。特别是，我们 打算从与 DNA 结合的蛋白质开始。任务是 (i) 预测 蛋白质中的 DNA 结合位点，以及 (ii) 将线程限制在子集 已发现结合区域的蛋白质。在接下来的步骤中，我们 希望使用通用的序列基序进行自动比较。 (5) 螺纹加工 整个基因组：第一个任务是找到整个基因组中的所有蛋白质 我们知道其结构的有机体。然而，我们的特殊优势 方法将是即使在没有实验的情况下也能找到遥远的相似之处 有关结构的信息。