Chen Liao Y
Department of Physics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
Biophys Chem. 2015 Mar;198:14-21. doi: 10.1016/j.bpc.2015.01.004. Epub 2015 Jan 14.
Plasmodium falciparum aquaporin (PfAQP) is a multifunctional channel protein in the plasma membrane of the malarial parasite that causes the most severe form of malaria infecting more than a million people a year. This channel protein facilitates transport of water and several solutes across the cell membrane. In order to better elucidate the fundamental interactions between PfAQP and its permeants and among the permeants, I conducted over three microseconds in silico experiments of atomistic models of the PfAQP-membrane system to obtain the free-energy profiles of five permeants (erythritol, water, glycerol, urea, and ammonia) throughout the amphipathic conducting pore of PfAQP. The profiles are analyzed in light of and shown to be consistent with the existent in vitro data. The binding affinities are computed using the free-energy profiles and the permeant fluctuations inside the channel. On this basis, it is predicted that erythritol, a permeant of PfAQP itself having a deep ditch in its permeation passageway, inhibits PfAQP's functions of transporting water and other solutes with an IC50 in the range of high nanomolars. This leads to the possibility that erythritol, a sweetener generally considered safe, may inhibit or kill the malarial parasite in vivo without causing undesired side effects. Experimental studies are hereby called for to directly test this theoretical prediction of erythritol strongly inhibiting PfAQP in vitro and possibly inhibiting P. falciparum in vivo.
恶性疟原虫水通道蛋白（PfAQP）是疟原虫质膜中的一种多功能通道蛋白，该疟原虫会引发最严重形式的疟疾，每年感染超过100万人。这种通道蛋白促进水和几种溶质跨细胞膜的运输。为了更好地阐明PfAQP与其渗透物之间以及渗透物之间的基本相互作用，我对PfAQP-膜系统的原子模型进行了超过三微秒的计算机模拟实验，以获得五种渗透物（赤藓糖醇、水、甘油、尿素和氨）在PfAQP两亲性传导孔中的自由能分布。根据现有体外数据对这些分布进行了分析，并表明它们是一致的。利用自由能分布和通道内渗透物的波动来计算结合亲和力。在此基础上，预测赤藓糖醇这种PfAQP自身的渗透物，其渗透通道中有一条深沟，会以高纳摩尔范围内的IC50抑制PfAQP运输水和其他溶质的功能。这就使得一般认为安全的甜味剂赤藓糖醇有可能在体内抑制或杀死疟原虫而不产生不良副作用。特此呼吁进行实验研究，以直接测试赤藓糖醇在体外强烈抑制PfAQP以及在体内可能抑制恶性疟原虫的这一理论预测。
