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Structures and Functions of Lipids and Membrane-active Molecules in Biological Environments

Posted: Mar. 01, 2023

Award Recipient: Michio Murata Osaka University

The study of the chemical structures of biomolecules with biological activities, especially small organic compounds, has a long history and remains an important field. With advances in analytical methods, the targets of structural analysis have expanded from solutions and crystals to lipid bilayers and molecular aggregates, allowing conformational and dynamic analysis of these heterogeneous systems. In particular, the structure of lipids and other natural products in biological membranes, the last frontier of life science, has largely been elucidated at the atomic level using solid-state NMR.

1. Conformation of raft lipids in model membranes
The structure and function of lipids in biological membranes have been the subject of much interdisciplinary research in recent years. In particular, lipid rafts, which are small, short-lived domains generated by the phase separation of membrane lipids, have attracted much attention as a platform for intercellular signal transduction. Eukaryotic biomembranes are complex molecular assemblies composed of thousands of lipid species and also of membrane lipids interacting with proteins, making their analytical investigation extremely difficult. On the other hand, structure studies at the atomic and molecular level often use model membranes with simplified lipid compositions to avoid this complexity. Dr. Murata used model membranes to solve this difficult problem of lipid rafts by elucidating the native structure and interactions of biomembrane lipids. He also attempted to reproduce the self-aggregates formed by lipid molecules in biomembranes using model membranes and to precisely elucidate the conformation and dynamics of the polar head, intermediate polar moiety, and hydrocarbon chain. For example, each methylene group of the fatty chain was regiospecifically deuterium-labeled by chemical synthesis, and the fluctuations and orientation of the lipids in the bilayer were closely examined by solid-state NMR. As a result, he experimentally demonstrated that densely packed clusters of only sphingomyelin, a typical raft lipid, occur in the presence of cholesterol, answering a long-standing question regarding the formation of lipid rafts on cell membranes.

2. Average orientation of branching lipids responsible for tolerance to thermal and osmotic changes in archaeal membranes
Phosphatidylglycerophosphate methyl ester (PGP-Me) from halophilic Halobacterium salinarum was taken as an archaeal membrane lipid, and the average stereo configuration of its methyl branching chain was determined. Using solid-state 2H NMR of PGP-Me partially deuterated at three locations in the methyl branch, he investigated the conformation and average orientations of the methyl and methylene groups in the hydrated bilayer membrane. Combining these results with molecular dynamics simulations by our collaborators, he found that the PGP-Me chains take a different average orientation than typical membrane lipids. In contrast, the C-C bonds of the PGP-Me chains alternated between parallel and tilted orientations relative to the membrane normal. This average orientation, characteristic of archaeal lipids, causes entanglement of methyl-branched chains and may play an important role in excellent thermal stability and high salt concentration tolerance.

3. Interaction and recognition mechanisms between fatty acids and their binding proteins
Fatty acid binding proteins (FABPs) are required for the transport of poorly water-soluble long-chain fatty acids into cytoplasmic mitochondria for energy production. Dr. Murata investigated how FABP recognizes the length of fatty acids composed of hydrocarbon chains. To solve this problem, he and his collaborators comprehensively evaluated the affinity between FABP and FABP using a calorimetric method and closely examined the lipid recognition mechanism of FABP by high-resolution crystal X-ray diffraction. As a result, it was found that heart-type FABP incorporates fatty acids of carbon numbers C10 to C18 , which are important substrates for β-oxidation in mitochondria, with almost the same affinity by increasing or decreasing the number of water molecules in the clusters of the binding pocket. These findings provide insight into the general mechanism by which proteins recognize a variety of lipids with different chain lengths.

4. Structure of self-assembly of biologically active natural products in membranes
He and his colleagues have long been studying the structures of natural organic compounds that bind to lipid bilayers and exhibit biological activity. For example, they have elucidated the molecular aggregates formed in membranes and their interactions with membrane lipids for the dinoflagellate antifungal amphidinol, the antibiotic amphotericin B, and plant-derived saponins. Of particular note is the recent success in determining the structure of the ion channel assembly of amphotericin B responsible for the pharmacological action by organic synthesis and solid-state NMR.

As described above, Dr. Murata has conducted pioneering research on the structural elucidation of biomolecules and their self-assembly and has played a leading role in recent breakthroughs in this field. Therefore, his achievements are truly remarkable, and he is deemed worthy of the Chemical Society of Japan Award.