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水平上识别这些关系，这是通过对它们的序列进行比对来实现的。然而，当结构已经确定时，这种关系可以通过公共区域的叠加来检测，这是一种称为结构对齐的技术。这两个过程都涉及挑战，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，我们继续努力从两个不同的方面满足这一需求。 首先，我们对我们的基准同源膜蛋白结构集进行了改进，称为HOMP。用于编译数据集的代码已被重写，使其更加精简，能够并行运行，从而允许随着可用的膜蛋白结构数据库继续其指数增长而在未来快速更新。虽然HOMEP的更新版尚未完成，但我们预计这一过程很快就会完成，届时数据集将通过我们的网站www.forrest Lab.org向公众提供。这些变化将促进再培训，从而改进我们的序列比对软件AlignMe。 其次，我们扩展了早期(手动)对膜蛋白已知结构中对称性的分析(Forrest，Annu Rev BiPhys 2015)，启动了一项系统研究，将现有的对称性分析工具(SymD和CEsymm)应用于这个新的HOMP数据集。这项工作有望识别对称和不对称膜蛋白中可能涉及其功能机制的模式和关系。

During evolution proteins retain common three-dimentional 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 alignment of their sequences. However, when structures have been determined, such relationships can be detected by superposition of common regions, a technique known as structure alignment. Both procedures involve 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 continued our efforts to address this need on two different fronts. First, we have made improvements to our benchmark set of homologous membrane protein structures, 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 exponential growth. Although the updated version of HOMEP is not yet complete, we expect this process to finish shortly, at which time the dataset will be made available to the public through our website, www.forrestlab.org. These changes will facilitate retraining and therefore improvements of our sequence alignment software, AlignMe. Second, we have expanded an earlier (manual) analysis of symmetries within known structures of membrane proteins (Forrest, Annu Rev Biophys 2015), by initiating a systematic study to apply available symmetry analysis tools (SymD and CEsymm) to this new HOMEP dataset. This work is expected to identify patterns and relationships in symmetrical and asymmetrical membrane proteins that may speak to their functional mechanisms.