Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, India.
PLoS One. 2019 Aug 2;14(8):e0220336. doi: 10.1371/journal.pone.0220336. eCollection 2019.
Intra-chain domain interactions are known to play a significant role in the function and stability of multidomain proteins. These interactions are mediated through a physical interaction at domain-domain interfaces (DDIs). With a motivation to understand evolution of interfaces, we have investigated similarities among DDIs. Even though interfaces of protein-protein interactions (PPIs) have been previously studied by structurally aligning interfaces, similar analyses have not yet been performed on DDIs of either multidomain proteins or PPIs. For studying the structural landscape of DDIs, we have used iAlign to structurally align intra-chain domain interfaces of domains. The interface alignment of spatially constrained domains (due to inter-domain linkers) showed that ~88% of these could identify a structural matching interface having similar C-alpha geometry and contact pattern despite that aligned domain pairs are not structurally related. Moreover, the mean interface similarity score (IS-score) is 0.307, which is higher compared to the average random IS-score (0.207) suggesting domain interfaces are not random. The structural space of DDIs is highly connected as ~84% of all possible directed edges among interfaces are found to have at most path length of 8 when 0.26 is IS-score threshold. At this threshold, ~83% of interfaces form the largest strongly connected component. Thus, suggesting that structural space of intra-chain domain interfaces is degenerate and highly connected, as has been found in PPI interfaces. Interestingly, searching for structural neighbors of inter-chain interfaces among intra-chain interfaces showed that ~86% could find a statistically significant match to intra-chain interface with a mean IS-score of 0.311. This implies that domain interfaces are degenerate whether formed within a protein or between proteins. The interface degeneracy is most likely due to limited possible ways of packing secondary structures. In principle, interface similarities can be exploited to accurately model domain interfaces in structure prediction of multidomain proteins.
链内结构域相互作用在多功能蛋白的功能和稳定性中起着重要作用。这些相互作用是通过结构域-结构域界面（DDI）的物理相互作用来介导的。为了了解界面的进化，我们研究了 DDI 之间的相似性。尽管之前已经通过结构上对齐接口来研究蛋白质-蛋白质相互作用（PPI）的接口，但尚未对多功能蛋白或 PPI 的 DDI 进行类似的分析。为了研究 DDI 的结构景观，我们使用 iAlign 来结构上对齐结构域内的链内结构域接口。由于结构域间的连接体，空间约束的结构域的接口对齐表明，尽管对齐的结构域对之间没有结构相关性，但这些结构域对中有 88%可以识别具有相似 C-α几何形状和接触模式的结构匹配接口。此外，平均接口相似性得分（IS-得分）为 0.307，高于平均随机 IS-得分（0.207），这表明结构域接口不是随机的。DDI 的结构空间是高度连接的，因为当 IS-得分阈值为 0.26 时，在所有可能的接口之间的定向边中，大约 84%的边的最大路径长度为 8。在这个阈值下，大约 83%的接口形成最大的强连通分量。这表明链内结构域接口的结构空间是退化的和高度连接的，这与 PPI 接口中发现的情况相似。有趣的是，在链内接口中搜索链间接口的结构邻居表明，大约 86%的链内接口可以找到具有统计学意义的匹配，其平均 IS-得分为 0.311。这意味着结构域接口在形成于蛋白质内部或蛋白质之间时是退化的。接口的退化很可能是由于包装二级结构的方式有限。原则上，可以利用接口相似性来准确地模拟多维蛋白结构预测中的结构域接口。
