The thermal stability of proteins can be altered when they interact with small molecules, other biomolecules or are subject to post-translation modifications. Thus monitoring the thermal stability of proteins under various cellular perturbations can provide insights into protein function, as well as potentially determine drug targets and off-targets. Thermal proteome profiling is a highly multiplexed mass-spectrommetry method for monitoring the melting behaviour of thousands of proteins in a single experiment. In essence, thermal proteome profiling assumes that proteins denature upon heating and hence become insoluble. Thus, by tracking the relative solubility of proteins at sequentially increasing temperatures, one can report on the thermal stability of a protein. Standard thermodynamics predicts a sigmoidal relationship between temperature and relative solubility and this is the basis of current robust statistical procedures. However, current methods do not model deviations from this behaviour and they do not quantify uncertainty in the melting profiles. To overcome these challenges, we propose the application of Bayesian functional data analysis tools which allow complex temperature-solubility behaviours. Our methods have improved sensitivity over the state-of-the art, identify new drug-protein associations and have less restrictive assumptions than current approaches. Our methods allows for comprehensive analysis of proteins that deviate from the predicted sigmoid behaviour and we uncover potentially biphasic phenomena with a series of published datasets.

中文翻译：

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热蛋白质组分析的贝叶斯半参数模型

当蛋白质与小分子，其他生物分子相互作用或进行翻译后修饰时，蛋白质的热稳定性可能会改变。因此，在各种细胞干扰下监测蛋白质的热稳定性可以提供对蛋白质功能的了解，并有可能确定药物靶标和脱靶标。热蛋白质组分析是一种高度复用的质谱法，可在单个实验中监测数千种蛋白质的融化行为。本质上，热蛋白质组谱分析假设蛋白质在加热时会变性，因此变得不可溶。因此，通过追踪蛋白质在依次升高的温度下的相对溶解度，可以报告蛋白质的热稳定性。标准热力学预测温度和相对溶解度之间呈S形关系，这是当前可靠的统计程序的基础。但是，当前的方法不能对这种行为的偏差进行建模，并且不能量化熔化曲线中的不确定性。为了克服这些挑战，我们建议应用贝叶斯功能数据分析工具，该工具可以实现复杂的温度溶解性行为。与目前的方法相比，我们的方法与现有技术相比具有更高的灵敏度，可以识别新的药物-蛋白质关联，并且具有较少的限制性假设。我们的方法可以对偏离预期的S型行为的蛋白质进行全面分析，并通过一系列已公开的数据集发现潜在的双相现象。