Computational design of environmental sensors for the potent opioid fentanyl.
Computational design of environmental sensors for the potent opioid fentanyl.
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DOI：
10.7554/elife.28909
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发表时间：
2017-09-19
期刊：
影响因子：
7.7
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Bick MJ;Greisen PJ;Morey KJ;Antunes MS;La D;Sankaran B;Reymond L;Johnsson K;Medford JI;Baker D
我们描述了结合强效镇痛剂芬太尼的蛋白质的计算设计。我们的方法采用了快速对接算法，以找到形状互补的配体在蛋白质支架的位置，然后通过设计周围的残基，以优化结合亲和力。最高亲和力结合剂的共晶结构揭示了高度预组织的结合位点，以及与设计模型密切一致的整体架构和配体位置。我们使用的设计，以产生植物传感器芬太尼通过耦合配体结合设计的稳定性。该方法通常可用于检测环境中的有毒疏水化合物。许多小分子，包括毒素和一些药物，具有灵活的结构，这使得难以检测和/或中和它们。例如，止痛药芬太尼可以旋转以采用许多形状。近年来，芬太尼类药物滥用日益普遍，该药物往往是非法生产的。芬太尼导致的死亡人数大幅上升，这为寻找检测这种药物和其他药物的新方法提供了强有力的理由。现在，Baker等人已经开发出能够检测芬太尼的新传感器。首先，根据已知的分子结构信息，确定了芬太尼最可能采用的11种形状。然后，一个计算机程序被用来设计蛋白质，这些蛋白质被预测会与这些最常见的形状强烈结合。接下来，在实验室中合成编码这些蛋白质的基因，并将其引入细菌中，细菌读取基因以构建蛋白质。类似于一把合适的锁和钥匙，新设计的蛋白质的形状必须与芬太尼分子的可能形状互补。Baker等人使用一种称为X射线晶体学的技术来可视化蛋白质的原子细节，并确认这些芬太尼结合剂与其相应的计算模型相匹配。然后将那些与芬太尼结合得最好的蛋白质工程化到植物细胞中，然后再工程化到整个植物中，以及当传感器检测到芬太尼时发出信号的报告系统。将来，这些专门合成的蛋白质可以整合到整个植物或其他系统中，以检测毒素和其他有害化学物质。这样的系统在医疗环境中和用于检测环境污染中将是令人感兴趣的。
We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment. Many small molecules, including toxins and some medicines, have flexible structures, which makes it difficult to detect and/or neutralize them. The pain medication fentanyl, for example, can rotate to adopt many shapes. In recent years, fentanyl drug abuse has become increasingly common, and the drug is often illegally produced. The number of deaths caused by fentanyl has risen greatly, which provides a strong reason to find new ways to detect this and other drugs. Now, Baker et al. have created new sensors that are able to detect fentanyl. First, the 11 most likely shapes that fentanyl could adopt were identified based on known information about the structure of the molecule. Then, a computer program was used to design proteins that were predicted to strongly bind to these most common shapes. Next, genes that coded for these proteins were synthesized in the laboratory and introduced into bacteria, which read the genes to build the proteins. Similar to a well-fitted lock and key, the shape of the newly designed protein had to complement a likely shape of the fentanyl molecule. Baker et al. used a technique called X-ray crystallography to visualize the proteins in atomic detail and confirm that these fentanyl-binders matched their corresponding computational models. Those proteins that bound fentanyl best were then engineered into plant cells, and later into whole plants, together with reporter systems that gave signals when the sensors detected fentanyl. In future, these specifically synthesized proteins could be integrated into entire panels of plants or other systems to detect toxins and other harmful chemicals. Such systems would be of interest in a medical setting and for detecting environmental contamination.