The second extracellular loops (ECL2s) of G-protein-coupled receptors (GPCRs) are often involved in GPCR functions, and their structures have important implications in drug discovery. However, structure prediction of ECL2 is difficult because of its long length and the structural diversity among different GPCRs. In this study, a new ECL2 conformational sampling method involving both template-based and ab initio sampling was developed. Inspired by the observation of similar ECL2 structures of closely related GPCRs, a template-based sampling method employing loop structure templates selected from the structure database was developed. A new metric for evaluating similarity of the target loop to templates was introduced for template selection. An ab initio loop sampling method was also developed to treat cases without highly similar templates. The ab initio method is based on the previously developed fragment assembly and loop closure method. A new sampling component that takes advantage of secondary structure prediction was added. In addition, a conserved disulfide bridge restraining ECL2 conformation was predicted and analytically incorporated into sampling, reducing the effective dimension of the conformational search space. The sampling method was combined with an existing energy function for comparison with previously reported loop structure prediction methods, and the benchmark test demonstrated outstanding performance.

中文翻译：

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GalaxyGPCRloop：G蛋白偶联受体的细胞外环的基于模板和从头开始的结构采样

G蛋白偶联受体（GPCR）的第二个细胞外环（ECL2）通常参与GPCR功能，其结构在药物发现中具有重要意义。但是，由于ECL2的长度长和不同GPCR之间的结构多样性，因此很难进行结构预测。在这项研究中，开发了一种新的ECL2构象采样方法，该方法涉及基于模板的采样和从头开始的采样。受到观察密切相关的GPCR的类似ECL2结构的启发，开发了一种基于模板的采样方法，该方法采用了从结构数据库中选择的环结构模板。引入了用于评估目标循环与模板的相似性的新度量，用于模板选择。一个从头还开发了循环抽样方法来治疗没有高度相似模板的病例。的从头计算方法是基于所述先前开发的片段组件和环路闭合方法。添加了利用二级结构预测优势的新采样组件。另外，预测了保守的二硫键抑制ECL2构象，并将其分析纳入了采样，从而减小了构象搜索空间的有效尺寸。采样方法与现有的能量函数相结合，可以与先前报告的回路结构预测方法进行比较，基准测试显示出出色的性能。