Protein rotamers refer to the conformational isomers taken by the side-chains of amino acids to accommodate specific structural folding environments. Since accurate modeling of atomic interactions is difficult, rotamer information collected from experimentally solved protein structures is often used to guide side-chain packing in protein folding and sequence design studies. Many rotamer libraries have been built in the literature but there is little quantitative guidance on which libraries should be chosen for different structural modeling studies. Here, we performed a comparative study of six widely used rotamer libraries and systematically examined their suitability for protein folding and sequence design in four aspects: (1) side-chain match accuracy, (2) side-chain conformation prediction, (3) de novo protein sequence design, and (4) computational time cost. We demonstrated that, compared to the backbone-dependent rotamer libraries (BBDRLs), the backbone-independent rotamer libraries (BBIRLs) generated conformations that more closely matched the native conformations due to the larger number of rotamers in the local rotamer search spaces. However, more practically, using an optimized physical energy function incorporated into a simulated annealing Monte Carlo searching scheme, we showed that utilization of the BBDRLs could result in higher accuracies in side-chain prediction and higher sequence recapitulation rates in protein design experiments. Detailed data analyses showed that the major advantage of BBDRLs lies in the energy term derived from the rotamer probabilities that are associated with the individual backbone torsion angle subspaces. This term is important for distinguishing between amino acid identities as well as the rotamer conformations of an amino acid. Meanwhile, the backbone torsion angle subspace-specific rotamer search drastically speeds up the searching time, despite the significantly larger number of total rotamers in the BBDRLs. These results should provide important guidance for the development and selection of rotamer libraries for practical protein design and structure prediction studies.

中文翻译：

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迈向蛋白质侧链包装的准确性和速度：对Rotamer文库的系统研究。

蛋白质旋转异构体是指氨基酸侧链采用的构象异构体，以适应特定的结构折叠环境。由于很难精确地建立原子相互作用的模型，因此从实验解析的蛋白质结构中收集的旋转异构体信息通常用于指导蛋白质折叠和序列设计研究中的侧链堆积。文献中已经建立了许多旋转异构体库，但是对于为不同的结构建模研究应选择哪种库，几乎没有定量指导。在这里，我们对六个广泛使用的旋转异构体文库进行了比较研究，并从四个方面系统地检查了它们对蛋白质折叠和序列设计的适用性：（1）侧链匹配准确性，（2）侧链构象预测，（3）de新蛋白序列设计，（4）计算时间成本。我们证明，与依赖于主链的旋转异构体文库（BBDRL）相比，不依赖于主链的旋转异构体文库（BBIRL）生成的构象与本地构象更接近，这是由于本地旋转异构体搜索空间中的大量旋转异构体所致。但是，更实际的是，使用结合到模拟退火蒙特卡洛搜索方案中的优化物理能函数，我们表明利用BBDRLs可以在蛋白质设计实验中提高侧链预测的准确性和序列重现率。详细的数据分析表明，BBDRL的主要优势在于从与单个主干扭转角子空间相关的旋转概率得出的能量项。该术语对于区分氨基酸同一性和氨基酸的旋转异构体构象很重要。同时，尽管BBDRL中的总旋转头数量明显增加，但主干扭转角子空间特定的旋转头搜索极大地加快了搜索时间。这些结果应为开发和选择用于实际蛋白质设计和结构预测研究的旋转异构体文库提供重要指导。