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

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.