Refining homology models by combining replica-exchange molecular dynamics and statistical potentials.
Refining homology models by combining replica-exchange molecular dynamics and statistical potentials.
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作者：
Zhu J;Fan H;Periole X;Honig B;Mark AE
提出了一种蛋白质同源性模型的全局优化方法。它结合了基于温度的复制交换分子动力学（REMD）的构象采样和模型选择的统计势的使用的优点。该协议使用21个模型进行了测试。其中14个是10个小蛋白质的模型，其高分辨率晶体结构是可用的，其余的是最近CASPR工作的目标。结果发现，REMD与目前可用的力场相结合，可以从高质量的同源模型开始采样近天然构象状态。在21个样品中，有15个样品的二级结构元件骨架RMSD（SSE RMSD）比起始值低0.5 ~ 1.0 μ m（平均0.82 μ m）。此外，当使用由两个统计势组成的简单评分函数对结构进行排序时，在21个案例中的11个案例中，在5个最佳排序结构中发现一个或多个结构的SSE-RMSD至少比起始值低0.2 μ m。最佳模型的SSE-RMSD平均改善为0.42 Å。然而，测试的评分函数都没有将具有最低SSE-RMSD的结构鉴定为最佳模型，尽管所有的评分函数都将天然构象鉴定为具有最低能量的构象。这表明，虽然所提出的协议被证明是有效的小蛋白质的高质量模型的细化，评分功能仍然是结构细化的主要限制因素之一。这方面和其他方面的方法可以进一步改进进行了讨论。
A protocol is presented for the global refinement of homology models of proteins. It combines the advantages of temperature-based replica-exchange molecular dynamics (REMD) for conformational sampling and the use of statistical potentials for model selection. The protocol was tested using 21 models. Of these 14 were models of 10 small proteins for which high-resolution crystal structures were available, the remainder were targets of the recent CASPR exercise. It was found that REMD in combination with currently available force fields could sample near-native conformational states starting from high-quality homology models. Conformations in which the backbone RMSD of secondary structure elements (SSE-RMSD) was lower than the starting value by 0.5 to 1.0 Å were found for 15 out of the 21 cases (average 0.82 Å). Furthermore, when a simple scoring function consisting of two statistical potentials was used to rank the structures, one or more structures with SSE-RMSD of at least 0.2 Å lower than the starting value was found among the 5 best ranked structures in 11 out of the 21 cases. The average improvement in SSE-RMSD for the best models was 0.42 Å. However, none of the scoring functions tested identified the structures with the lowest SSE-RMSD as the best models although all identified the native conformation as the one with lowest energy. This suggests that while the proposed protocol proved effective for the refinement of high-quality models of small proteins scoring functions remain one of the major limiting factors in structure refinement. This and other aspects by which the methodology could be further improved are discussed.
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