CAREER: Supramolecular Chemistry at the Interface of Lipid Bilayers and Water

该奖项部分由2021年美国救援计划法案（公法117-2）资助。在化学系大分子、超分子和纳米化学项目的支持下，杜兰大学的Nathalie Busschaert将研究生物膜中与脂质相互作用的小分子背后的基本超分子化学。脂质是一类重要的生物化合物，具有多种生理功能，如能量储存、提供疏水屏障和信号转导等。因此，需要能够与某些类型的生物脂相互作用的小分子。然而，最大的挑战是，脂质主要以“脂质双分子层”的形式存在于膜中，具有不同寻常的物理性质，使脂质结合分子的形成复杂化。Busschaert博士的目标是设计新颖的小分子，可以选择性地与一种类型的脂质结合，而不是其他类型的脂质，并使用模型脂质体系统研究各种物理膜特性对这种结合事件的影响。该项目预计将有助于建立设计分子的一般指导方针，这些分子可以选择性地结合脂质双层内的特定脂质，通过探索脂质作为一个不寻常的目标，可以对超分子化学领域产生更广泛的影响，有助于阐明脂质生物化学和生物物理学，促进人类健康，并为涉及膜的任何应用提供基础知识。这项工作预计将对女性在STEM领域的参与产生进一步更广泛的影响，因为Busschaert博士将监督一些超分子化学启发的活动，以增加女性和少数民族在各级教育中对STEM的参与。该项目的中心假设是，脂质头基团与传统的超分子目标（如磷酸阴离子和铵阳离子）相当，但在设计脂质结合分子时需要考虑脂质双分子层的不同寻常的物理性质。到目前为止，只有少数关于小分子选择性地与某些类型的脂质头基团结合的报道。然而，在大多数情况下，宿主分子与感兴趣的脂质的结合是在有机溶液或一种脂质体中确定的。这样的研究忽略了生物膜中的脂质多样性，也没有考虑到脂质双分子层独特物理性质的影响。脂质头基团的结合发生在膜-水界面，这使其成为一种不同寻常的超分子相互作用。界面区域部分水化，因此呈现出与在水和/或有机溶液中观察到的超分子相互作用不同的情况。此外，脂质双层显示流体、液晶状态，既不显示溶液动力学，也不显示固态动力学。中心假设将通过合成各种化合物来结合特定的脂质头基团，然后使用各种技术来表征这些化合物与基于脂质体的模型系统的结合，包括核磁共振（NMR），紫外-可见光谱，表面等离子体共振和等温滴定量热法。这些活性旨在帮助确定疏水性、物理膜性质（例如，脂质形状、酰基链长度、膜曲率）和多价性对脂质双分子层结合的影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in part under the American Rescue Plan Act of 2021 (Public Law 117-2).With support from the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Nathalie Busschaert of Tulane University will study the fundamental supramolecular chemistry behind small molecules that interact with lipids in biological membranes. Lipids are an important class of biological compounds and play a role in a variety of physiological functions, such as energy storage, providing a hydrophobic barrier, and signal transduction. There is therefore a need for small molecules that can interact with certain types of biological lipids. The biggest challenge, however, is that lipids mostly reside in membranes as 'lipid bilayers' that possess unusual physical properties complicating the development of lipid-binding molecules. Dr. Busschaert aims to design novel small molecules that can selectively bind to one type of lipid over other types of lipids and study the effect of various physical membrane properties on this binding event using model liposome-based systems. The project is anticipated to help establish general guidelines for the design of molecules that can selectively bind to specific lipids within lipid bilayers, which can have a broader impact on the field of supramolecular chemistry by exploring lipids as an unusual target, help elucidate lipid biochemistry and biophysics, advance human health and provide fundamental knowledge for any application involving membranes. This work is expected to have a further broader impact on the participation of women in STEM fields, as Dr. Busschaert will oversee a number of supramolecular chemistry inspired activities to increase the participation of women and minorities in STEM at every level of education.The central hypothesis of the project is that lipid head-groups are comparable to traditional supramolecular targets such as phosphate anions and ammonium cations, but that the unusual physical properties of lipid bilayers need to be considered when designing lipid-binding molecules. So far, there have only been a few reports of small molecules binding selectively to certain types of lipid head-groups. However, in most cases the binding of the host molecules with the lipid of interest was determined in organic solution or in one type of liposome. Such investigations ignore the lipid diversity in biological membranes and do not take into account the effects of the unique physical properties of lipid bilayers. The binding of lipid head-groups takes place at the membrane-water interface, which makes it an unusual type of supramolecular interaction. The interface region is partially hydrated and is therefore presents a different situation from that observed with supramolecular interactions in water and or in organic solution. Furthermore, lipid bilayers display a fluid, liquid crystalline state that displays neither solution kinetics nor solid state dynamics. The central hypothesis will be tested by synthesizing a variety of compounds designed to bind to specific lipid head-groups, and then characterizing the binding of these compounds with model liposome-based systems using a variety of techniques, including nuclear magnetic resonance (NMR), UV-Vis spectroscopy, surface plasmon resonance and isothermal titration calorimetry. These activities are designed to help identify the effect of hydrophobicity, physical membrane properties (e.g., lipid shape, acyl chain length, membrane curvature), and multivalency on binding to lipid bilayers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.