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，尽管氨基酸的基本序列可能会发生巨大的差异。这种关系甚至可以在给定的蛋白质结构内部发现，由重复和重复定义的元素产生。因此，确定两种蛋白质之间的关系，或同一蛋白质的两个区域之间的关系，可能具有极高的价值。大多数情况下，需要在一级氨基酸编码水平上识别这些关系，这是通过排列它们的序列来实现的。然而，当结构确定后，可以通过覆盖公共区域来检测这种关系，这种技术称为结构对齐。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的时候。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这些工具。

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.