Murail Samuel, Vasiliu Tudor, Neamtu Andrei, Barboiu Mihail, Sterpone Fabio, Baaden Marc
MTi (Molécules Thérapeutiques In Silico), INSERM UMR-S973, University Paris Diderot, France.
Faraday Discuss. 2018 Sep 28;209(0):125-148. doi: 10.1039/c8fd00046h.
Artificial water channels (AWCs) have been designed for water transport across membranes with the aim to mimic the high water permeability observed for biological systems such as aquaporins (∼108-109 water molecules per s per channel), as well as their selectivity to reject ion permeation at the same time. Recent works on designed self-assembling alkylureido-ethylimidazole compounds forming imidazole-quartet channels (I-quartets), have shown both high water permeability and total ionic-rejection. I-quartets are thus promising candidates for further development of AWCs. However, the molecular mechanism of water permeation as well as I-quartet organization and stability in a membrane environment need to be fully understood to guide their optimal design. Here, we use a wide range of all-atom molecular dynamics (MD) simulations and their analysis to understand the structure/activity relationships of the I-quartet channels. Four different types with varying alkyl chain length or chirality have been studied in a complex fully hydrated lipid bilayer environment at both microsecond and nanosecond scale. Microsecond simulations show two distinct behaviors; (i) two out of four systems maintain chiral dipolar oriented water wires, but also undergo a strong reorganization of the crystal shape, (ii) the two other I-quartet channels completely lose the initial organization, nonetheless keeping a water transport activity. Short MD simulations with higher time resolution were conducted to characterize the dynamic properties of water molecules in these model channels and provided a detailed hypothesis on the molecular mechanism of water permeation. The ordered confined water was characterized with quantitative measures of hydrogen-bond life-time and single particle dynamics, showing variability among I-quartet channels. We will further discuss the underlying assumptions, currently based on self-aggregation simulations and crystal patches embedded in lipid bilayer simulations and attempt to describe possible alternative approaches to computationally capture the water permeation mechanism and the self-assembly process of these AWCs.
人工水通道（AWCs）被设计用于跨膜输水，目的是模拟生物系统（如水通道蛋白，每个通道每秒约有10⁸ - 10⁹个水分子通过）所具有的高透水性，同时还要具备排斥离子渗透的选择性。近期关于设计自组装烷基脲基 - 乙基咪唑化合物形成咪唑四重态通道（I - 四重态）的研究表明，该通道既具有高透水性又能完全排斥离子。因此，I - 四重态有望成为进一步开发人工水通道的候选对象。然而，要指导其优化设计，就需要充分了解水渗透的分子机制以及I - 四重态在膜环境中的组织和稳定性。在此，我们运用广泛的全原子分子动力学（MD）模拟及其分析方法来理解I - 四重态通道的结构/活性关系。在微秒和纳秒尺度下，我们研究了四种不同类型的、具有不同烷基链长度或手性的I - 四重态通道，它们处于完全水合的复杂脂质双层环境中。微秒模拟显示出两种不同的行为：（i）四个系统中的两个保持手性偶极取向的水线，但晶体形状也会发生强烈重组；（ii）另外两个I - 四重态通道完全失去初始结构，但仍保持输水活性。我们进行了具有更高时间分辨率的短MD模拟，以表征这些模型通道中水分子的动力学特性，并对水渗透的分子机制提出了详细的假设。通过氢键寿命和单粒子动力学的定量测量对有序受限水进行了表征，结果表明I - 四重态通道之间存在差异。我们将进一步讨论目前基于自聚集模拟和嵌入脂质双层模拟中的晶体斑块所做的潜在假设，并尝试描述可能的替代方法，以便通过计算捕捉这些人工水通道的水渗透机制和自组装过程。
