Elucidating Novel Topological Features in Protein Structures

阐明蛋白质结构中的新拓扑特征

• 批准号: 7300043
• 负责人: Todd O Yeates
• 金额: $ 26.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300043
• 关键词: Address; Adopted; Affect; Algorithms; Area; Beds; Circular Dichroism; Citrate (si)-Synthase; Communities; Complex; Computer Analysis; Computer software; Condition; Databases; Fluorescence; Genetic Recombination; Internet; Link; Methods; Numbers; Operative Surgical Procedures; Organism; Property; Protein Analysis; Proteins; Research Personnel; Role; Site-Directed Mutagenesis; Structure; Testing; Time; Ursidae Family; Work; base; computer program; design; dimer; human disease; insight; interest; link protein; novel; programs; protein folding; protein structure; research study; theories

DESCRIPTION (provided by applicant): Natural proteins adopt complex folded configurations. How they reach their folded configurations is a subject of intense interest. In addition, proteins must maintain stability in their native configurations, and there are open questions about how this is achieved, especially by proteins that must survive harsh conditions. Proteins that adopt particularly complex structures provide unique insights into both of these questions. This proposal focuses on the discovery and analysis of proteins whose structures reveal topological complexity, such as knotting, and linking of protein chains. Such proteins provide valuable test cases and challenging questions in the areas of protein folding and stabilization. Until recently, the possibility of naturally knotted protein chains was considered so problematic as to be nearly forbidden. But recent computational analysis of the growing structural database has revealed a few deeply knotted protein folds, and these have drawn the interest of experimentalists and theorists alike. In this proposal: (1) Using a new algorithm, we reveal a novel type of topologically complexity in the database of known protein structures: slip-knots. These are cases where a knot is created by some part of the protein chain, while the chain in its entirety appears to be unknotted. These cases, of which we have identified several, have escaped previous knot analysis. (2) We add to the set of known topologically complex proteins by determining new structures from a particular organism where we have evidence that linking and knotting are relatively common; (3) We develop a protein design strategy for converting knotted proteins into unknotted ones and vice-versa, in order to provide a test bed for studying the stabilizing effects of complex topological features in proteins. Supporting biophysical experiments are included. Biomedical relevance: The connections between human disease and protein destabilization and unfolding are becoming increasingly clear. At the present time, there are still open questions about the rules and mechanisms of protein folding. The proteins to be studied here possess unique features that make them valuable in efforts to achieve a fundamental understanding of protein structure and stability.

描述（由申请人提供）：天然蛋白质采用复杂的折叠构型。它们如何达到折叠的形态是一个非常有趣的课题。此外，蛋白质必须保持其天然构型的稳定性，而如何实现这一点，特别是必须在恶劣条件下生存的蛋白质，还存在一些悬而未决的问题。采用特别复杂结构的蛋白质为这两个问题提供了独特的见解。该提案的重点是发现和分析蛋白质的结构揭示拓扑复杂性，如打结，蛋白质链的连接。这些蛋白质在蛋白质折叠和稳定化领域提供了有价值的测试案例和具有挑战性的问题。直到最近，自然打结的蛋白质链的可能性被认为是如此有问题，以至于几乎被禁止。但是最近对不断增长的结构数据库的计算分析揭示了一些深深打结的蛋白质折叠，这些都引起了实验学家和理论家的兴趣。在本提案中：（1）使用一种新的算法，我们揭示了已知蛋白质结构数据库中的一种新型拓扑复杂性：滑结。在这些情况下，蛋白质链的某些部分产生了一个结，而整个链似乎是解开的。这些情况下，其中我们已经确定了几个，已经逃脱了以前的结分析。(2)我们添加到一组已知的拓扑复杂的蛋白质，确定新的结构，从一个特定的生物体，我们有证据表明，连接和打结是比较常见的;（3）我们开发了一个蛋白质的设计策略，将打结的蛋白质转化为未打结的，反之亦然，为了提供一个测试床，研究蛋白质中复杂的拓扑特征的稳定作用。支持生物物理实验包括在内。生物医学相关性：人类疾病与蛋白质不稳定和展开之间的联系越来越清晰。目前，关于蛋白质折叠的规则和机制仍有一些悬而未决的问题。这里要研究的蛋白质具有独特的功能，使它们在努力实现对蛋白质结构和稳定性的基本理解方面具有价值。