Youn Taeyeol, Ehsan Muhammad, Hariharan Parameswaran, Li Xianglan, Moon Youngsun, Ahmed Waqar, Byrne Bernadette, Liu Xiangyu, Guan Lan, Chae Pil Seok
Major in Bionano Engineering, School of Bio-Pharmaceutical Convergence, Hanyang University, Ansan, 155-88, Republic of Korea.
Department of Cell Physiology and Molecular Biophysics, Center for Membrane Protein Research, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, 79430, USA.
J Mater Chem B. 2025 Sep 8. doi: 10.1039/d5tb01342a.
Membrane proteins are essential bio-macromolecules involved in numerous critical biological processes and serve as therapeutic targets for a wide range of modern pharmaceuticals. Small amphipathic molecules, called detergents or surfactants, are widely used for the isolation and structural characterization of these proteins. A key requirement for such studies is their ability to maintain membrane protein stability in aqueous solution, a task where conventional detergents often fall short. While many new detergents have been developed based on novel molecular scaffolds, comparatively little effort has been made to enhance detergent performance through rational modification of existing structures, largely due to the limited availability of guiding design principles and strategies. In this study, we refined previously developed butane-1,2,3,4-tetraol based maltosides (BTMs), using two structural modification strategies, head/tail group-swapping and the introduction of hydrophobic unsymmetry. The resulting group-swapped (GS)-BTMs exhibited distinctive physical properties compared to the original BTM, including differences in water-solubility (∼7 to >10 wt%), critical aggregation concentration (5 to 15 μM), and self-assembly size (7.6 to 34.2 nm). When evaluated using model membrane proteins, including the human adrenergic receptor (βAR), symmetric GS-BTMs (, GS-BTM-C11 and GS-BTM-C12) showed superior performance relative to the original BTM-C11 and benchmark detergents (DDM and LMNG). The unsymmetric variants, such as GS-BTM-C14,10 and GS-BTM-C15,9, further improved protein stability. These findings highlight group-swapping and hydrophobic unsymmetry as effective strategies for enhancing detergent performance. This work demonstrates how minimal structural modifications can impact detergent properties and efficacy, providing valuable insights for the development of improved detergents from existing molecular frameworks.
膜蛋白是参与众多关键生物过程的重要生物大分子，也是多种现代药物的治疗靶点。称为去污剂或表面活性剂的小两亲分子被广泛用于这些蛋白质的分离和结构表征。此类研究的一个关键要求是它们能够在水溶液中维持膜蛋白的稳定性，而传统去污剂在这项任务中往往表现不佳。虽然基于新型分子支架开发了许多新型去污剂，但通过对现有结构进行合理修饰来提高去污剂性能的努力相对较少，这主要是由于指导设计原则和策略的可用性有限。在本研究中，我们使用两种结构修饰策略，即头/尾基团交换和引入疏水不对称性，对先前开发的基于丁烷-1,2,3,4-四醇的麦芽糖苷（BTM）进行了改进。与原始BTM相比，所得的基团交换（GS）-BTM表现出独特的物理性质，包括水溶性（约7至>10 wt%）、临界聚集浓度（5至15 μM）和自组装尺寸（7.6至34.2 nm）的差异。当使用包括人肾上腺素能受体（βAR）在内的模型膜蛋白进行评估时，对称的GS-BTM（GS-BTM-C11和GS-BTM-C12）相对于原始的BTM-C11和基准去污剂（DDM和LMNG）表现出优异的性能。不对称变体，如GS-BTM-C14,10和GS-BTM-C15,9，进一步提高了蛋白质稳定性。这些发现突出了基团交换和疏水不对称性作为提高去污剂性能的有效策略。这项工作展示了最小的结构修饰如何影响去污剂的性质和功效，为从现有分子框架开发改进的去污剂提供了有价值的见解。
