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，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鉴定这些关系，这是通过比对它们的序列来实现的。然而，当结构已经确定时，可以通过公共区域的叠加来检测这种关系，这是一种称为结构对齐的技术。这两种方法都存在挑战，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，我们继续努力在两个不同方面满足这一需要。 首先，我们对我们的同源膜蛋白结构的基准集（称为HOMEP）进行了改进。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，从而随着可用膜蛋白结构的数据库继续呈指数级增长，允许快速更新。虽然HOMEP的更新版本尚未完成，但我们预计这一过程将很快完成，届时数据集将通过我们的网站www.forrestlab.org向公众提供。这些变化将促进重新培训，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 Biophys 2015），通过启动系统研究将可用的对称性分析工具（SymD和CEsymm）应用于这个新的HOMEP数据集。这项工作有望确定对称和不对称膜蛋白的模式和关系，这些模式和关系可能与它们的功能机制有关。

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.