Integration of small-angle X-ray scattering data into structural modeling of proteins and their assemblies.
Integration of small-angle X-ray scattering data into structural modeling of proteins and their assemblies.
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DOI：
10.1016/j.jmb.2008.07.074
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发表时间：
2008-10-17
影响因子：
5.6
通讯作者：
Sali, Andrej
中科院分区：
文献类型：
--
作者：
Foerster, Friedrich;Webb, Benjamin;Krukenberg, Kristin A.;Tsuruta, Hiro;Agard, David A.;Sali, Andrej
关键词：
结构生物学中的一个主要挑战是分别确定多结构域蛋白质和组装体中结构域和蛋白质的构型。为了最大限度地提高这些模型的准确性和精确度，应考虑所有可用的数据。小角X射线散射（SAXS）可以有效地提供有关蛋白质及其组装体形状的低分辨率实验数据。因此，我们将SAXS配置文件集成到我们的软件中，通过满足空间约束来建模蛋白质及其组装。具体来说，我们模型的四级结构的多结构域蛋白质与结构上定义的刚性结构域以及四级结构的二元复合物的结构上定义的刚性蛋白质。除了SAXS配置文件和组件的结构，我们采用立体化学的限制和原子距离依赖的统计潜力。评分函数通过有偏蒙特卡罗协议进行优化，包括拟牛顿和模拟退火方案。最终预测对应于许多独立计算的解决方案的最大聚类中的最佳评分解决方案。为了量化基于其SAXS谱确定四级结构的程度，我们使用了12个模拟实例的基准以及同源四聚体D-木糖异构酶的实验SAXS谱。SAXS相关的评分函数的优化通常会导致准确的模型，如果足够精确的近似组成刚体;否则，最好的评分模型可能有显着的错误。因此，SAXS配置文件可以在蛋白质和组件的结构表征中发挥有用的作用，如果它们与其他数据相结合，并明智地使用。我们的集成的SAXS配置文件到建模的空间约束的满意度，将促进进一步整合不同种类的数据，蛋白质及其组件的结构测定。
A major challenge in structural biology is to determine the configuration of domains and proteins in multi-domain proteins and assemblies, respectively. To maximize the accuracy and precision of these models, all available data should be considered. Small angle x-ray scattering (SAXS) efficiently provides low-resolution experimental data about the shapes of proteins and their assemblies. Thus, we integrated SAXS profiles into our software for modeling proteins and their assemblies by satisfaction of spatial restraints. Specifically, we model the quaternary structures of multidomain proteins with structurally defined rigid domains as well as quaternary structures of binary complexes of structurally defined rigid proteins. In addition to SAXS profiles and the component structures, we employ stereochemical restraints and an atomic distance-dependent statistical potential. The scoring function is optimized by a biased Monte Carlo protocol, including quasi-Newton and simulated annealing schemes. The final prediction corresponds to the best scoring solution in the largest cluster of many independently calculated solutions. To quantify how well the quaternary structures are determined based on their SAXS profiles, we used a benchmark of 12 simulated examples as well as an experimental SAXS profile of the homo-tetramer D-xylose isomerase. Optimization of the SAXS-dependent scoring function generally results in accurate models, if sufficiently precise approximations for the constituent rigid bodies are available; otherwise, the best scoring models can have significant errors. Thus, SAXS profiles can play a useful role in the structural characterization of proteins and assemblies, if they are combined with additional data and used judiciously. Our integration of a SAXS profile into modeling by satisfaction of spatial restraints will facilitate further integration of different kinds of data for structure determination of proteins and their assemblies.
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