Deuteration distribution estimation with improved sequence coverage for HX/MS experiments
Deuteration distribution estimation with improved sequence coverage for HX/MS experiments
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DOI：
10.1093/bioinformatics/btq165
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发表时间：
2010-06-15
期刊：
影响因子：
5.8
通讯作者：
Hamprecht, Fred A.
中科院分区：
文献类型：
--
作者：
Lou, Xinghua;Kirchner, Marc;Hamprecht, Fred A.
动机：时间分辨氢交换（HX）和质谱（MS）是研究蛋白质结构、动力学和相互作用的关键技术。HX实验提供了感兴趣的蛋白质的肽序列的氘代水平的时间依赖性分布。对尽可能多的肽片段的这种分布的稳健和完整的估计有助于理解动态蛋白质水平的HX行为。目前，这个数据解释步骤仍然是一个瓶颈，在整个HX/MS workflow.Results：我们提出了HeXicon，一种新的算法工作流程，自动氘代分布估计在增加序列覆盖率。基于L-1正则化特征提取程序，HeXicon提取完整的氘代分布，这允许洞察蛋白质可能的双峰交换行为，而不仅仅是每个时间点的平均氘代。此外，它能够解决不适定的估计问题，产生稀疏和物理上合理的结果。HeXicon利用现有的肽序列信息，通过从已知蛋白质序列衍生的肽候选物的推断列表来增强。结合平衡灵敏度和特异性的监督分类程序，HeXicon可以提供具有更高序列覆盖率的结果。
Motivation: Time-resolved hydrogen exchange (HX) followed by mass spectrometry (MS) is a key technology for studying protein structure, dynamics and interactions. HX experiments deliver a time-dependent distribution of deuteration levels of peptide sequences of the protein of interest. The robust and complete estimation of this distribution for as many peptide fragments as possible is instrumental to understanding dynamic protein-level HX behavior. Currently, this data interpretation step still is a bottleneck in the overall HX/MS workflow.Results: We propose HeXicon, a novel algorithmic workflow for automatic deuteration distribution estimation at increased sequence coverage. Based on an L-1-regularized feature extraction routine, HeXicon extracts the full deuteration distribution, which allows insight into possible bimodal exchange behavior of proteins, rather than just an average deuteration for each time point. Further, it is capable of addressing ill-posed estimation problems, yielding sparse and physically reasonable results. HeXicon makes use of existing peptide sequence information, which is augmented by an inferred list of peptide candidates derived from a known protein sequence. In conjunction with a supervised classification procedure that balances sensitivity and specificity, HeXicon can deliver results with increased sequence coverage.