Development and assessment of methods for membrane protein structure prediction

膜蛋白结构预测方法的开发和评估

• 批准号: 9563174
• 负责人: Lucy Forrest
• 金额: $ 60.1万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9563174
• 关键词: Amino Acid Sequence; Amino Acids; Benchmarking; Cell membrane; Code; Comparative Study; Computer software; Computing Methodologies; Crystallization; Data Set; Databases; Development; Dimensions; Distant; Elements; Encyclopedias; Environment; Evolution; Eye; FDA approved; Future; Genes; Genome; Growth; Homologous Gene; Homology Modeling; Human; Hydrophobicity; Intuition; Manuals; Membrane; Membrane Proteins; Methodology; Methods; Modeling; Molecular Conformation; Nature; Online Systems; Organism; Pattern; Pharmaceutical Preparations; Procedures; Protein Analysis; Proteins; Protocols documentation; Resolution; Running; Sequence Alignment; Structure; Syncope; Techniques; Update; Work; base; data visualization; database structure; improved; insight; online resource; protein function; protein structure; protein structure prediction; tool

During evolution, proteins retain common three-dimensional structural features, even though the underlying sequence of amino acids can diverge dramatically. Such relationships can even be found internally within a given protein structure, arising from duplication and repetition of defined elements. Identifying relationships between two proteins, or two regions of the same protein, that are very distantly related, therefore, can be of extremely high value. Most often, identification of those relationships is needed on the level of primary amino acid codes, which is achieved by aligning their sequences. However, when structures have been determined, such relationships can be detected by overlaying common regions, a technique known as structure alignment. Both procedures involve considerable challenges, especially when the similarities between the two proteins are small. Consequently, there remains a need for methods that reliably and accurately compute sequence or structure alignments. In the past year, we have combined efforts from two different fronts in developing such tools. First, we have made improvements to our benchmark set of homologous membrane protein structures, earlier versions of which were called HOMEP. The code used to compile the dataset has been rewritten to make it more streamlined and able to run in parallel, allowing for fast future updates as the database of available membrane protein structures continues its pseudo-exponential growth. These changes will facilitate retraining of, and therefore improvements in, our sequence alignment software, AlignMe developed previously. Second, we have expanded upon an earlier (manual) analysis of symmetries in structures of membrane proteins, by initiating a systematic study that applies available symmetry analysis tools (SymD and CEsymm) to known protein structures. This work is expected to identify patterns and relationships in symmetrical and asymmetrical membrane proteins and to reveal how those symmetries relate to functional mechanisms. These two analyses have now been combined into a single database called EncoMPASS (Encyclopedia for Membrane Proteins Analyzed by Structure and Symmetry). The combination allows us to leverage information about structural neighbors in order to improve the quality and applicability of the symmetry analysis. Moreover, we have made visualization of the data easy through a public webserver hosted at https://encompass.ninds.nih.gov.

在进化过程中，蛋白质保留了共同的三维结构特征，即使氨基酸的基本序列可以显着不同。这种关系甚至可以在给定的蛋白质结构内部发现，这是由定义元素的复制和重复引起的。因此，识别两个蛋白质或同一蛋白质的两个区域之间的关系，这是非常遥远的关系，可以具有极高的价值。大多数情况下，需要在一级氨基酸代码的水平上识别这些关系，这是通过比对它们的序列来实现的。然而，当已经确定结构时，可以通过覆盖公共区域来检测这种关系，这是一种称为结构对准的技术。这两种方法都涉及相当大的挑战，特别是当两种蛋白质之间的相似性很小时。因此，仍然需要可靠且准确地计算序列或结构比对的方法。在过去一年中，我们从两个不同方面共同努力，开发了这些工具。 首先，我们对同源膜蛋白结构的基准集进行了改进，其早期版本被称为HOMEP。用于编译数据集的代码已被重写，以使其更加精简并能够并行运行，从而允许随着可用膜蛋白结构的数据库继续其伪指数增长而快速更新。这些变化将有助于重新训练，因此改进，我们的序列比对软件，AlignMe以前开发的。 其次，我们已经扩大了早期（手动）分析膜蛋白结构的对称性，通过启动一个系统的研究，适用于已知的蛋白质结构的对称性分析工具（SymD和CEsymm）。这项工作预计将确定对称和不对称膜蛋白的模式和关系，并揭示这些对称性如何与功能机制相关。 这两个分析现在已经被合并到一个名为EncoMPASS（结构和对称性分析膜蛋白百科全书）的数据库中。这种结合使我们能够利用结构邻居的信息，以提高对称性分析的质量和适用性。此外，我们还通过https://encompass.ninds.nih.gov托管的公共网络服务器轻松实现了数据的可视化。