Experimentally assessing molecular dynamics sampling of the protein native state conformational distribution.
Experimentally assessing molecular dynamics sampling of the protein native state conformational distribution.
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DOI：
10.1016/j.bpc.2012.02.002
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发表时间：
2012-04
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.
酰胺氢交换反应所表现出的构象的急性敏感性提供了一个有价值的测试模型合奏的物理准确性开发代表玻尔兹曼分布的蛋白质的天然状态。一些泛素的分子动力学研究预测了一个良好的人口过渡紧转弯前的蛋白酶体指导的多聚泛素化赖氨酸48的主要网站。酰胺交换反应性分析表明，这种转变是103倍罕见的比这些预测。更引人注目的是，对于最近1 ms MD模拟牛胰胰蛋白酶抑制剂预测的最多的新构象盆地（占总数的13%），实验氢交换数据表明人口低于10−6。最复杂的努力，直接将实验的限制到模型蛋白质系综的推导已被应用到泛素，如最近存放的三个研究（PDB代码2NR2，2K39和2KOX）所示。利用广泛的实验NOE的约束，这三个合奏产生一个适度更准确的预测汇率的高度暴露的酰胺比一个标准的无约束的分子模拟。然而，对于不太频繁暴露的酰胺氢，2NR2合奏提供速率预测相比，无约束的MD合奏没有改善。其他两个NMR约束的合奏表现明显较差，要么低估（2K0X）或高估（2K39）的构象多样性的程度。
The acute sensitivity to conformation exhibited by amide hydrogen exchange reactivity provides a valuable test for the physical accuracy of model ensembles developed to represent the Boltzmann distribution of the protein native state. A number of molecular dynamics studies of ubiquitin have predicted a well-populated transition in the tight turn immediately preceding the primary site of proteasome-directed polyubiquitylation Lys 48. Amide exchange reactivity analysis demonstrates that this transition is 103-fold rarer than these predictions. More strikingly, for the most populated novel conformational basin predicted from a recent 1 ms MD simulation of bovine pancreatic trypsin inhibitor (at 13% of total), experimental hydrogen exchange data indicates a population below 10−6. The most sophisticated efforts to directly incorporate experimental constraints into the derivation of model protein ensembles have been applied to ubiquitin, as illustrated by three recently deposited studies (PDB codes 2NR2, 2K39 and 2KOX). Utilizing the extensive set of experimental NOE constraints, each of these three ensembles yields a modestly more accurate prediction of the exchange rates for the highly exposed amides than does a standard unconstrained molecular simulation. However, for the less frequently exposed amide hydrogens, the 2NR2 ensemble offers no improvement in rate predictions as compared to the unconstrained MD ensemble. The other two NMR-constrained ensembles performed markedly worse, either underestimating (2KOX) or overestimating (2K39) the extent of conformational diversity.
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影响因子：
2.9
作者：
Antosiewicz, J;McCammon, JA;Gilson, MK
通讯作者：
Gilson, MK
影响因子：
2.9
作者：
Hernandez, Griselda;Anderson, Janet S.;LeMaster, David M.
通讯作者：
LeMaster, David M.
影响因子：
5.6
作者：
ANTOSIEWICZ, J;MCCAMMON, JA;GILSON, MK
通讯作者：
GILSON, MK
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
16.6
作者：
EIGEN, M
通讯作者：
EIGEN, M