Assessing the native state conformational distribution of ubiquitin by peptide acidity.
Assessing the native state conformational distribution of ubiquitin by peptide acidity.
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DOI：
10.1016/j.bpc.2010.10.006
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发表时间：
2010-12
影响因子：
3.8
通讯作者：
LeMaster, David M.
中科院分区：
文献类型：
--
作者：
Hernandez, Griselda;Anderson, Janet S.;LeMaster, David M.
关键词：
在平衡状态下，蛋白质的每一个能量上可行的构象都以非零的概率出现。因此，蛋白质柔性的定量分析与确定该构象分布的适当玻尔兹曼加权是同义的。溶剂暴露的酰胺氢的交换反应性随构象变化很大，而短寿命的肽阴离子中间体意味着对构象运动的动力学不敏感。在泛素的模型构象集合中暴露良好的酰胺在交换率上变化百万倍，连续介质方法可以预测其rmsd为3。然而，许多更罕见的暴露的酰胺的交换率显着高估在PDB沉积的2K 39和2KN 5泛素合奏，而2NR 2合奏预测在很大程度上是一致的玻尔兹曼加权构象分布采样的水平为1%。对于一个给定的酰胺氢和交换速率常数为该残留物的溶剂可访问的构象的分数之间的相关性提供了一个有用的监测的完整性程度，与给定的合奏已采样的能量可访问的构象空间。这些交换预测与每个系综偏离一组46个泛素X射线结构的程度相关。Kolmogorov-Smirnov分析内和合奏间成对结构rmsd值的分布，有助于确定一个子合奏2K 39，消除了高估氢交换率观察到的完整合奏。将实验的限制到构象采样过程的相对优点相比，使用这些限制作为过滤器，以选择与实验数据一致的亚群。
At equilibrium, every energetically feasible conformation of a protein occurs with a non-zero probability. Quantitative analysis of protein flexibility is thus synonymous with determining the proper Boltzmann-weighting of this conformational distribution. The exchange reactivity of solvent-exposed amide hydrogens greatly varies with conformation, while the short-lived peptide anion intermediate implies an insensitivity to the dynamics of conformational motion. Amides that are well-exposed in model conformational ensembles of ubiquitin vary a million-fold in exchange rates which continuum dielectric methods can predict with an rmsd of 3. However, the exchange rates for many of the more rarely exposed amides are markedly overestimated in the PDB-deposited 2K39 and 2KN5 ubiquitin ensembles, while the 2NR2 ensemble predictions are largely consistent with those of the Boltzmann-weighted conformational distribution sampled at the level of 1%. The correlation between the fraction of solvent-accessible conformations for a given amide hydrogen and the exchange rate constant for that residue provides a useful monitor of the degree of completeness with which a given ensemble has sampled the energetically accessible conformational space. These exchange predictions correlate with the degree to which each ensemble deviates from a set of 46 ubiquitin X-ray structures. Kolmogorov-Smirnov analysis for the distribution of intra- and inter-ensemble pairwise structural rmsd values assisted the identification of a subensemble of 2K39 that eliminates the overestimations of hydrogen exchange rates observed for the full ensemble. The relative merits of incorporating experimental restraints into the conformational sampling process is compared to using these restraints as filters to select subpopulations consistent with the experimental data.
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