Refinement of Highly Flexible Protein Structures using Simulation-Guided Spectroscopy
Refinement of Highly Flexible Protein Structures using Simulation-Guided Spectroscopy
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DOI：
10.1002/anie.201810462
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发表时间：
2018-12-21
影响因子：
16.6
通讯作者：
Kasson, Peter M.
中科院分区：
文献类型：
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作者：
Hays, Jennifer M.;Kieber, Marissa K.;Kasson, Peter M.
高度灵活的蛋白质对结构测定提出了特殊的挑战，因为它们是多结构的但不是无序的，因此它们的构象集合对于理解功能至关重要。由于多个构象群的光谱测量通常提供稀疏数据，因此实验选择是构象细化的限制因素。已经开发出一种基于分子模拟和信息论的方法来选择哪些实验最能完善构象系综。这种方法在三种柔性蛋白质上进行了测试。对于存在明确机制假说的蛋白质，系统地鉴定了检验该假说的实验。当现有数据不能产生这样的机制假设时，就确定了在构象细化方面显着优于结构引导方法的实验。当精炼具有挑战性的、不确定的蛋白质构象集合时，这种方法具有特殊的优势。
Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. A molecular simulations- and information-theory based approach to select which experiments best refine conformational ensembles has been developed. This approach was tested on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, experiments that test this hypothesis were systematically identified. When available data did not yield such mechanistic hypotheses, experiments that significantly outperform structure-guided approaches in conformational refinement were identified. This approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles.