Conformations of musk odorants and their binding to human musk receptors

在化学和生物系统中，结构和功能紧密相连，理解它们之间的关系是技术进步的基础。了解分子所采用的不同构象对于深入了解它们的化学和生物学功能至关重要。然而，尽管它具有巨大的重要性，构象分析仍然是许多过程的突出挑战。在这个项目中，我们提出了一种新的方法来解释构象灵活性，并将其应用于长期存在的麝香嗅觉受体（OR）相互作用的问题。麝香气味剂是香水中的关键化合物，因为它们具有独特的感官和固定品质。天然麝香是具有酮和内酯官能团的大环。自20世纪初以来，它们就被用于香水中，但由于提取困难和合成复杂，它们非常昂贵。因此，人们多次尝试开发具有类似嗅觉和固定特性的新化合物，这导致了其他种类麝香的出现。其中许多被发现是有毒和对环境有害的，并且正在逐渐从消费品中移除。因此，设计和开发新的可生物降解麝香仍然具有巨大的工业兴趣。由于缺乏大环麝香和麝香or的结构数据，对决定麝香- or结合和麝香气味的分子特征的理解受到阻碍。构象柔韧性是气味剂和ORs的一个重要特征，是一个主要因素。大环麝香具有多种构象，这使得传统的光谱技术无法对其进行分析。预计补偿金在结构上也将具有灵活性。它们的重要性随着时间的推移而增加，因为它们已经在鼻子外的组织中被发现，并被认为是癌症的驱动因素。在这个项目中，我们将通过首次识别大环麝香的构象，并在一个改进的人类麝香OR模型上确定它们的对接和结合趋势，来解决提高我们对麝香气味理解的挑战。我们将使用尖端的光谱技术和多尺度计算方法。我们与香料行业的领导者之一合作，将使我们能够研究与工业相关的麝香，并利用行业对结构-活性关系应用的观点。我们的研究结果将使我们对麝香气味的分子特征和相互作用的认识取得重大突破，并为合理设计环境安全的麝香铺平道路。我们将开发的工具和结果将进一步有利于其他领域的研究，包括可持续合成、香料、结构生物学和分子建模。

Structure and function are intimately linked in chemical and biological systems, and understanding their relationship underpins technological progress. Knowledge of the different conformations adopted by molecules is crucial to gain insight into their chemical and biological functions. However, despite its tremendous importance, conformational analysis remains an outstanding challenge for many processes. In this project we propose a novel approach to account for conformational flexibility and apply it to the long standing question of musk-olfactory receptor (OR) interactions.Musk odorants are key compounds in perfumery due to their distinctive sensual notes and fixatives qualities. Natural musks are macrocycles with ketone and lactone functional groups. They have been used in perfumery since the beginning of the 20th century but they were very expensive due of the difficulties in their extraction and their complex synthesis. There were thus numerous attempts to develop new compounds with similar olfactory and fixative properties, which led to the appearance of other classes of musks. Many of these were found to be toxic and environmentally harmful, and are gradually being removed from use in consumer goods. Therefore designing and developing new biodegradable musks is still of huge industrial interest. Progress on understanding the molecular features that determine musk-OR binding and musk smell has been hampered by the lack of structural data on macrocyclic musks and musk ORs. Conformational flexibility, an important characteristic of both odorants and ORs, is a major factor. Macrocyclic musks are expected to adopt many conformations, which has prevented their analysis by traditional spectroscopic techniques. ORs are also expected to be structurally flexible. Their importance has grown over the years, since they have been found in tissues outside the nose and have been proposed as drivers of cancer.In this project we will address the challenge of advancing our understanding of musk smell by identifying macrocyclic musks' conformations for the first time, and determining their docking and binding trends on a refined model of a human musk OR. We will use a cutting-edge spectroscopic technique and multiscale computational methods. Our partnership with one of the leaders in the fragrance and flavor industry will allow us to investigate musks of industrial relevance and to get advantage of the industry's viewpoint on the application of structure-activity relationships. Our results will make a significant breakthrough in our knowledge of the molecular features and interactions mediating musk smell, and will pave the way to a rational design of environmentally safe musks. The tools and results we will develop will be of further benefit to other areas of research including sustainable synthesis, perfumery, structural biology and molecular modelling.