Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction
Backrub-like backbone simulation recapitulates natural protein conformational variability and improves mutant side-chain prediction
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DOI：
10.1016/j.jmb.2008.05.023
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发表时间：
2008-07-18
影响因子：
5.6
通讯作者：
Kortemme, Tanja
中科院分区：
文献类型：
--
作者：
Smith, Colin A.;Kortemme, Tanja
在蛋白质模拟和设计中引入有效的骨架采样是提高计算蛋白质建模精度的重要一步。最近对高分辨率晶体结构的分析提出了一种称为背摩擦的新模型，用于描述在晶格中观察到的局部，铰链状的替代主链和侧链构象。该模型涉及到c - α原子之间围绕轴的内部骨干旋转。基于这一观察结果，我们在罗塞塔结构预测和设计程序中实现了一种受背摩启发的采样方法。我们使用三种不同的测试来评估这种骨干柔韧性模型。首先，我们展示了Rosetta backrub模拟再现了模型所基于的高分辨率晶体结构中主链和侧链构象之间的相关性。作为背擦采样的第二次测试，我们表明，相对于单独的固定骨干旋转采样，骨干灵活性提高了预测点突变侧链构象的准确性。最后，我们证明了三磷酸异构酶环6的背摩擦取样可以捕捉到溶液中观察到的开状态和闭状态之间的毫秒/微秒振荡。我们的研究结果表明，背部摩擦取样捕获了天然蛋白质中发生的相当大一部分局部构象变化。应用这种简单的骨干运动模型可以显著改善蛋白质设计和局部蛋白质柔韧性的原子模拟。(C) 2008 Elsevier Ltd版权所有。
Incorporation of effective backbone sampling into protein simulation and design is an important step in increasing the accuracy of computational protein modeling. Recent analysis of high-resolution crystal structures has suggested a new model, termed backrub, to describe localized, hinge-like alternative backbone and side-chain conformations observed in the crystal lattice. The model involves internal backbone rotations about axes between C-alpha atoms. Based on this observation, we have implemented a backrub-inspired sampling method in the Rosetta structure prediction and design program. We evaluate this model of backbone flexibility using three different tests. First, we show that Rosetta backrub simulations recapitulate the correlation between backbone and side-chain conformations in the high-resolution crystal structures upon which the model was based. As a second test of backrub sampling, we show that backbone flexibility improves the accuracy of predicting point-mutant side-chain conformations over fixed backbone rotameric sampling alone. Finally, we show that backrub sampling of triosephosphate isomerase loop 6 can capture the millisecond/microsecond oscillation between the open and closed states observed in solution. Our results suggest that backrub sampling captures a sizable fraction of localized conformational changes that occur in natural proteins. Application of this simple model of backbone motions may significantly improve both protein design and atomistic simulations of localized protein flexibility. (C) 2008 Elsevier Ltd. All rights reserved.