Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-193, Aveiro, Portugal.
Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.
Phys Chem Chem Phys. 2018 Aug 15;20(32):20796-20811. doi: 10.1039/c8cp02576b.
A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical mono-squaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured.
本文报道了一系列四组脒衍生化合物的跨膜氯离子传输的综合实验和理论研究，这些化合物具有不同程度的氟化、收敛 N-H 结合单元数量和构象形状。通过在 POPC 双层中的量子描述符和分子动力学模拟，对这些小分子合成物在脂质体中的氯离子结合和传输能力进行了合理化。基于三齿 tren 的化合物具有三个脒结合基序，对氯离子具有高亲和力，将阴离子从膜模型内的水分子中隔离出来，并防止其释放到水相中，这与实验中没有观察到转运活性一致。相比之下，对称的单脒具有适度的氯离子结合亲和力，能够在水相或膜界面水平上结合和释放氯离子，这与实验观察到的高转运活性一致。与这些游离转运体及其氯离子配合物在磷脂双层中扩散相关的 PMF 曲线表明，氯离子的协助转运在热力学上是有利的。
