Predicting flexible loop regions that interact with ligands: the challenge of accurate scoring.
Predicting flexible loop regions that interact with ligands: the challenge of accurate scoring.
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DOI：
10.1002/prot.23199
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发表时间：
2012-01
影响因子：
2.9
通讯作者：
Lill, Markus A.
中科院分区：
文献类型：
--
作者：
Danielson, Matthew L.;Lill, Markus A.
柔性环区在许多蛋白质的生物学功能中起关键作用，并且已被证明参与配体结合。在基于结构的药物设计的背景下，如果环能够与配体相互作用，则使用或预测不正确的环构型可能对研究有害。三个蛋白质系统，每个具有至少一个柔性环区域在接近已知的结合位点，被选择用于环预测使用CorLps程序;六个残基的环区域从磷酸核糖甘氨酰胺甲酰转移酶（GART），两个9个残基的环区域从细胞色素P450（CYP 119），和一个11个残基的环区域从烯醇化酶被选择用于环预测。这项研究的结果表明，在CorLps程序中实现的基于几何的DFIRE评分函数在任何蛋白质系统中都不能准确地对类似天然的预测环构型进行排名。为了改善天然样预测环构型的排序，使用MM/GBSA和优化MM/GBSA-dsr评分函数对具有和不具有结合配体的预测环进行重新排序。一般而言，单次快照MM/GBSA评分提供了天然样环配置的最佳排名。基于所提出的评分函数分析，类似于本地环路配置的最佳排名仍然是一个困难的挑战，并且“最佳”评分函数的选择似乎取决于系统。
Flexible loop regions play a critical role in the biological function of many proteins and have been shown to be involved in ligand binding. In the context of structure-based drug design, using or predicting an incorrect loop configuration can be detrimental to the study if the loop is capable of interacting with the ligand. Three protein systems, each with at least one flexible loop region in close proximity to the known binding site, were selected for loop prediction using the CorLps program; a six residue loop region from phosphoribosylglycinamide formyltransferase (GART), two nine residue loop regions from cytochrome P450 (CYP) 119, and an eleven residue loop region from enolase were selected for loop prediction. The results of this study indicate that the statistically-based DFIRE scoring function implemented in the CorLps program did not accurately rank native-like predicted loop configurations in any protein system. In an attempt to improve the ranking of the native-like predicted loop configurations, the MM/GBSA and the Optimized MM/GBSA-dsr scoring functions were used to re-rank the predicted loops with and without bound ligand. In general, single snapshot MM/GBSA scoring provided the best ranking of native-like loop configurations. Based on the scoring function analyses presented, the optimal ranking of native-like loop configurations is still a difficult challenge and the choice of the “best” scoring function appears to be system dependent.
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