Temperature artifacts in protein structures bias ligand-binding predictions.
Temperature artifacts in protein structures bias ligand-binding predictions.
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DOI：
10.1039/d1sc02751d
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发表时间：
2021-09-01
期刊：
影响因子：
8.4
通讯作者：
Fischer M
中科院分区：
文献类型：
--
作者：
Bradford SYC;El Khoury L;Ge Y;Osato M;Mobley DL;Fischer M
X射线晶体学是解析构象系综的金标准，这些构象系综对于蛋白质功能、配体发现和计算方法的发展具有重要意义。然而，相关的构象状态可能会错过在常见的低温（cryo）数据收集温度，但可以在室温下填充。为了评估温度对结构和计算发现的影响，我们系统地研究了T4溶菌酶L99A腔中的结构和计算主力蛋白质构象变化对温度和配体结合的响应。尽管对这种蛋白质进行了数十年的研究，但转向RT揭示了新的全球和局部结构变化。这些包括发现一个载脂蛋白螺旋构象，这是隐藏在低温，但相关的配体结合，改变侧链和配体构象。为了评估温度诱导的蛋白质和配体变化对计算中结构信息效用的影响，我们评估了温度如何误导采用冷冻结构进行验证的计算方法。我们发现，当比较模拟结构只是实验低温结构，隐藏的成功和失败往往被忽视。当在配体结合预测中使用结构信息时，粗对接和严格的结合自由能计算都受到温度效应的影响。冷冻人工制品限制计算结构的效用的趋势在五种不同的蛋白质类中保持不变。我们的研究结果表明，单独查阅低温结构数据时要谨慎，因为温度伪影可能会隐藏错误并阻止成功的计算预测，这可能会误导发现生物活性分子的计算方法的开发和应用。蛋白质结构中的温度伪影通过误导发现生物活性分子的计算方法的验证和应用而影响计算中结构信息的效用。
X-ray crystallography is the gold standard to resolve conformational ensembles that are significant for protein function, ligand discovery, and computational methods development. However, relevant conformational states may be missed at common cryogenic (cryo) data-collection temperatures but can be populated at room temperature. To assess the impact of temperature on making structural and computational discoveries, we systematically investigated protein conformational changes in response to temperature and ligand binding in a structural and computational workhorse, the T4 lysozyme L99A cavity. Despite decades of work on this protein, shifting to RT reveals new global and local structural changes. These include uncovering an apo helix conformation that is hidden at cryo but relevant for ligand binding, and altered side chain and ligand conformations. To evaluate the impact of temperature-induced protein and ligand changes on the utility of structural information in computation, we evaluated how temperature can mislead computational methods that employ cryo structures for validation. We find that when comparing simulated structures just to experimental cryo structures, hidden successes and failures often go unnoticed. When using structural information in ligand binding predictions, both coarse docking and rigorous binding free energy calculations are influenced by temperature effects. The trend that cryo artifacts limit the utility of structures for computation holds across five distinct protein classes. Our results suggest caution when consulting cryogenic structural data alone, as temperature artifacts can conceal errors and prevent successful computational predictions, which can mislead the development and application of computational methods in discovering bioactive molecules. Temperature artifacts in protein structures impact the utility of structural information in computation by misleading validation and application of computational methods in discovering bioactive molecules.
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DOI：
10.1107/s0907444905034207
发表时间：
2006-01-01
影响因子：
2.2
作者：
Garman, EF;Owen, RL
通讯作者：
Owen, RL
影响因子：
8.4
作者：
Gapsys V;Pérez-Benito L;Aldeghi M;Seeliger D;van Vlijmen H;Tresadern G;de Groot BL
通讯作者：
de Groot BL
影响因子：
3.3
作者：
Boresch, S;Tettinger, F;Karplus, M
通讯作者：
Karplus, M
影响因子：
4.3
作者：
Eastman P;Swails J;Chodera JD;McGibbon RT;Zhao Y;Beauchamp KA;Wang LP;Simmonett AC;Harrigan MP;Stern CD;Wiewiora RP;Brooks BR;Pande VS
通讯作者：
Pande VS
影响因子：
5.5
作者：
Deng, Yuqing;Roux, Benoit
通讯作者：
Roux, Benoit