Development and assessment of methods for membrane protein structure prediction

在进化过程中，蛋白质保留了共同的三维结构特征，尽管潜在的氨基酸序列可能会有很大的差异。这种关系甚至可以在给定的蛋白质结构中找到，这种关系是由定义的元件的复制和重复引起的。因此，识别两个蛋白质之间的关系，或同一蛋白质的两个区域之间的关系，具有非常高的价值。大多数情况下，需要在初级氨基酸编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，当确定了结构后，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齐的技术。这两个过程都涉及到相当大的挑战，特别是在两种蛋白质之间的相似性很小的情况下。因此，仍然需要可靠和准确地计算序列或结构比对的方法。在过去的一年里，我们从两个不同的方面共同努力开发了这些工具。 首先，我们对我们的同源膜蛋白结构的基准集进行了改进，其早期版本被称为HOMP。用于编译数据集的代码已被重写，使其更精简，能够并行运行，从而允许随着可用膜蛋白结构数据库继续其伪指数增长而在未来快速更新。这些变化将促进我们之前开发的序列比对软件AlignMe的再培训，从而改进我们的软件。 其次，我们通过将现有的对称性分析工具(SymD和CEsymm)应用于已知蛋白质结构的系统研究，扩展了对膜蛋白质结构对称性的早期(手动)分析。这项工作有望识别对称性和非对称性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。 这两种分析现在已经被合并到一个名为Enneass(按结构和对称性分析的膜蛋白百科全书)的数据库中。这一组合使我们能够利用有关结构邻居的信息来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

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.