构建人工跨膜传输系统来模拟通道蛋白的结构与功能不仅能为人们理解通道蛋白的传输机理提供简单的理论模型，而且有助于新型药物的开发，具有重要的科学意义和应用前景。已报道的人工跨膜传输系统主要针对K+, Na+, Cl-和水分子，开发高选择性的质子传输系统仍极具挑战。近些年，分子机器的快速发展使得人们拥有更多的手段从分子层面上来精确把控分子的运动，从而模拟宏观的功能。但分子机器在跨膜传输领域的应用尚处在萌芽阶段，有待进一步的开发。本项目拟基于分子机器的概念将质子识别单元连接到稳定的跨膜分子骨架上来构建两类人工质子转运体——分子楼梯和分子轮盘，通过识别单元之间对质子的捕获和释放的动态接力来实现质子的跨膜传输。同时，利用癌细胞膜内外特有的质子梯度，将质子转运体应用于抗癌治疗中。该项研究不仅能拓展分子机器在跨膜传输领域的应用，也有望为低毒副作用的抗癌新药的开发提供有价值的参考。

Developing artificial transmembrane transporting systems that mimic the structures and functions of channel proteins not only provides theoretical models for understanding the complicated transmembrane ion transporting mechanism but also plays a significant role in novel drug discovery. Over the past 4 decades, artificial transmembrane transporting systems that enable fast conductance of K+, Na+, Cl- and water molecules have been reported. Nevertheless, developing artificial ion transporters able to efficiently and highly selectively transport protons remains a major challenge. The recent burgeon of molecular machines offers numerous strategies to precisely manipulate the motion of molecules at molecular level to mimic the functions in the macroscopic world. However, the application of molecular machines in transmembrane ion transporting is still in its infancy. In this proposal, two unique classes of molecular-machine-inspired artificial proton transporters, termed ‘molecular ladders’ and ‘molecular roulette’ will be developed by incorporating a series of rationally designed proton recognition units into a rigid transmembrane scaffold. Protons are transported across the membrane through a dynamic catching and releasing relay process among the proton recognition units under a transmembrane proton gradient. Given the fact that there exists a significant proton gradient across cancer cell membranes, but not the normal cells, these artificial proton transporters would offer a novel means of cancer killing with minimum cytotoxicity and side effects toward normal cells. Successful execution of the proposed research not only expands the application of molecular machines in transmembrane ion transporting, but also offers new scientific grounds based on which potential anticancer drugs could be identified via a novel mechanism.