分子梭协助离子跨膜运输的机理研究

采用增强采样分子动力学模拟研究了一轮烷型分子梭协助K⁺跨膜转运的机制, 该轮烷由两亲性的轴和套在轴上的大冠醚环及连接在大冠醚环上的小冠醚环构成, 轴上有3个带正电的结合位点. 通过计算穿梭过程的自由能变化, 探索了溶剂(氯仿、 乙腈、 水、 氯仿-乙腈)以及中间结合位点对该轮烷穿梭运动的影响, 并分析了中间位点在其携带K⁺穿越细胞膜(采用水-氯仿-水模拟)过程中的重要作用. 结果表明, 改变溶剂不会改变轮烷(不携带K⁺)的运动模式, 但随着溶剂极性的增加穿梭所需克服的自由能能垒显著降低; 在氯仿-乙腈混合溶剂中, 中间结合位点的质子化状态, 不影响轮烷(不携带K⁺)的穿梭能垒; 然而在模拟细胞膜的环境中, 该结合位点的质子化与去质子化相比大幅降低了穿梭的能垒, 促进了K⁺的跨膜转运, 表明中间位点的质子化对于离子转运至关重要, 进一步分析表明轮烷中大环穿梭和小环摆动的协同作用, 也是加速离子跨膜转运的另一关键因素.

Mechanism of Ion Transport Across Membranes Assisted by Molecular Shuttles

The mechanism of K⁺ transmembrane transport assisted by a rotaxane-based molecular shuttle was studied by advanced enhanced sampling molecular dynamics simulations. The rotaxane consisted of an amphiphilic axel， a large crown ether wheel sliding on the axle， and a linked small crown ether carrier. There were three positively charged binding sites on the axel. By calculating the free-energy change of the shuttle process， the effects of solvents（chloroform， acetonitrile， water， and chloroform-acetonitrile） and the middle binding site on the shuttle movement of the rotaxane were explored. Furthermore， the important role of the middle bin- ding site in transmembrane ion transport across cell membranes（using water-chloroform-water to simulate） was analyzed. The results indicate that changing the solvent does not alter the movement mode of the rotaxane （without K⁺）， but as the polarity of the solvent increases， the free energy barrier against the shuttle significantly decreases. In the chloroform-acetonitrile mixed solvent， the protonation state of the middle binding site does not affect the free energy barrier against shuttling of the rotaxane（without K⁺）. However， in the environment of the simulated cell membrane， compared with deprotonation， the protonation of this binding site significantly decreases the free energy barrier of shuttling and facilitates the transport of the K⁺ across the membrane， indicating that the protonation of the middle binding site is paramount importance for ion translocation. Further analysis shows that the cooperation between the shuttling movement of the large ring and the swinging movement of the small ring constitutes another key factor in accelerating transmembrane ion transport.