Progress and challenges in high-resolution refinement of protein structure models
Progress and challenges in high-resolution refinement of protein structure models
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DOI：
10.1002/prot.20376
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发表时间：
2005-04-01
影响因子：
2.9
通讯作者：
Baker, D
中科院分区：
文献类型：
--
作者：
Misura, KMS;Baker, D
即使在具有正确拓扑结构的蛋白质模型的背景下，在从头结构预测中实现原子水平的准确性也提出了一个巨大的挑战。高分辨率细化是对力场精度和采样方法的基本测试，其在比较建模和从头预测环境中的有限成功突出了当前方法的局限性。我们构建了四个测试，以确定我们当前方法中的瓶颈，并指导在这个具有挑战性的领域取得进展。前三次试验表明，在我们的改进模拟条件下，理想的原生结构是稳定的，并且改进方案可以显著降低扰动原生结构的均方根偏差（RMSD）。在第四个测试中，我们将改进方案应用于新生模型，并表明可以根据它们的能量来识别准确的模型，并且在一些情况下，许多埋藏侧链采用了原生构象。我们还发现，改进的新模型和天然结构之间的主链和侧链构象的差异主要局限于环区和天然结构具有罕见特征的区域，如罕见的转子或β链之间的非典型氢键。精炼的新生模型通常比精炼的理想化天然结构具有更高的能量，这表明在凝聚态下对局部主链构象和侧链排列进行采样是主要障碍。(C) 2005 Wiley-Liss, Inc。
Achieving atomic level accuracy in de novo structure prediction presents a formidable challenge even in the context of protein models with correct topologies. High-resolution refinement is a fundamental test of force field accuracy and sampling methodology, and its limited success in both comparative modeling and de novo prediction contexts highlights the limitations of current approaches. We constructed four tests to identify bottlenecks in our current approach and to guide progress in this challenging area. The first three tests showed that idealized native structures are stable under our refinement simulation conditions and that the refinement protocol can significantly decrease the root mean square deviation (RMSD) of perturbed native structures. In the fourth test we applied the refinement protocol to de novo models and showed that accurate models could be identified based on their energies, and in several cases many of the buried side chains adopted native-like conformations. We also showed that the differences in backbone and side-chain conformations between the refined de novo models and the native structures are largely localized to loop regions and regions where the native structure has unusual features such as rare rotamers or atypical hydrogen bonding between beta-strands. The refined de novo models typically have higher energies than refined idealized native structures, indicating that sampling of local backbone conformations and side-chain packing arrangements in a condensed state is a primary obstacle. (C) 2005 Wiley-Liss, Inc.