Intruding into the midnight zone of protein comparisons

闯入蛋白质比较的午夜区域

• 批准号: 6636639
• 负责人: BURKHARD ROST
• 金额: $ 26.61万
• 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/6636639
• 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 总结例如结构相似性。所有蛋白质对的绝大多数 相似的结构填充了“午夜区域”，即它们的序列也有所不同 对于基于序列的比较而言，很多。在这里，我们建议改进，扩展和 专门的方法结合了序列比对，结构预测和 功能信息。目标是完全揭开隐藏的相似性 通过可靠的自动工具测序的生物。到我们的尽头 项目，生命所实现的大多数蛋白质家族的序列将 据说可用。我们希望我们的系统能正确检测到 其中大多数的关系。 （1）基于预测的螺纹将序列对准与预测 二级结构和可访问性找到远程相似之处。我们希望 通过比较家庭，可以大大提高检测和对齐精度 与家庭而不是单一蛋白质。 （2）大约三分之一的蛋白质 在蠕虫和苍蝇中，似乎很长的地区缺乏常规的二级结构。 我们希望开发一种量身定制的方法，以可靠地检测和比较 地区。 （3）当前的方法没有发现极度分歧的相似之处 膜蛋白。我们建议开发一种结合膜的方法 与膜蛋白的分类进行螺纹。 （4）自序列以来 在暮光区及以下的比较是一项极其要求的任务，大多数 现有方法的准确性非常低。实际上，专家比较 正在研究的蛋白质对之间的功能方面。我们想 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。任务将是（i）预测 蛋白质中的DNA结合位点，以及（ii）将螺纹限制为子集 发现结合区域的蛋白质。在接下来的步骤中，我们 希望使用一般序列图案进行自动比较。 （5）线程 整个基因组：第一个任务是在整个中找到所有蛋白质 我们知道结构的生物体。但是，我们的特殊边缘 方法是在没有实验的情况下找到遥远的相似性 有关结构的信息。