Computations of Fold Changes in Evolution of Proteins

蛋白质进化倍数变化的计算

• 批准号: 6936040
• 负责人: Nick V. Grishin
• 金额: $ 28.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936040
• 关键词: biochemical evolution; computer assisted sequence analysis; computer simulation; conformation; mathematical model; molecular biology information system; protein folding; protein protein interaction; structural biology

DESCRIPTION (provided by applicant): Existence of homologous proteins that fold into globally different structures signifies an alternative to the concept that structures are more conserved than sequences and demonstrates that protein structures can evolve and change, thus possibly generating new folds and topologies. Our understanding of fold changes in evolution is currently limited to a number of illustrious examples contributed by both experimental studies and computational analysis of available protein structures. Preliminary results demonstrate that structural changes in evolution are more common than is usually accepted. We were able to define four potential mechanisms of fold changes in evolution: insertion deletion/substitution of structural elements, circular permutation, strand invasion, hairpin flip/swap. It is necessary to clarify the scope of these events and to perform a comprehensive analysis of sequence and structure data to find all instances of such changes and classify them. We will undertake comprehensive homology searches for the sequences from proteins families with known structure to find statistically significant sequence similarity links between proteins with different folds. We will analyze the nature of the differences and catalogue possible mechanisms of fold changes in evolution of protein structures. Finally, we will perform in silico evolution of model proteins under functional constraints and compare the results to those deduced from the analysis of natural sequences and structures.

描述（由申请人提供）：折叠成全球结构的同源蛋白的存在表示概念的替代方案，即结构比序列更保守，并证明蛋白质结构可以发展和变化，从而可能产生新的折叠和拓扑。我们对进化的折叠变化的理解目前仅限于实验研究和可用蛋白质结构的计算分析所贡献的许多杰出例子。初步结果表明，进化的结构变化比通常接受的更为普遍。我们能够定义折叠变化的四个潜在机制：插入结构元件的插入缺失/取代，圆形排列，链入侵，发夹夹/交换。有必要阐明这些事件的范围，并对序列和结构数据进行全面分析，以查找此类更改的所有实例并对其进行分类。我们将对具有已知结构的蛋白质家族的序列进行全面的同源搜索，以发现具有不同折叠的蛋白质之间具有统计学意义的序列相似性。我们将分析蛋白质结构演变折叠变化的差异和分类机制的性质。最后，我们将在功能约束下进行模型蛋白的计算机演变，并将结果与​​自然序列和结构分析得出的结果进行比较。