Atkovska Kalina, Hub Jochen S
University of Goettingen, Institute for Microbiology and Genetics, Goettingen, 37077, Germany.
University of Goettingen, Göttingen Center for Molecular Biosciences, Goettingen, 37077, Germany.
Sci Rep. 2017 Sep 20;7(1):12027. doi: 10.1038/s41598-017-11437-0.
Formate-nitrite transporters (FNTs) facilitate the translocation of monovalent polyatomic anions, such as formate and nitrite, across biological membranes. FNTs are widely distributed among pathogenic bacteria and eukaryotic parasites, but they lack human homologues, making them attractive drug targets. The mechanisms and energetics involved in anion permeation across the FNTs have remained largely unclear. Both, channel and transporter mode of function have been proposed, with strong indication of proton coupling to the permeation process. We combine molecular dynamics simulations, quantum mechanical calculations, and pK calculations, to compute the energetics of the complete permeation cycle of an FNT. We find that anions as such, are not able to traverse the FNT pore. Instead, anion binding into the pore is energetically coupled to protonation of a centrally located histidine. In turn, the histidine can protonate the permeating anion, thereby enabling its release. Such mechanism can accommodate the functional diversity among the FNTs, as it may facilitate both, export and import of substrates, with or without proton co-transport. The mechanism excludes proton leakage via the Grotthuss mechanism, and it rationalises the selectivity for weak acids.
甲酸 - 亚硝酸盐转运蛋白（FNTs）促进单价多原子阴离子（如甲酸和亚硝酸盐）跨生物膜的转运。FNTs广泛分布于病原菌和真核寄生虫中，但它们在人类中缺乏同源物，这使其成为有吸引力的药物靶点。阴离子通过FNTs渗透的机制和能量学在很大程度上仍不清楚。有人提出了通道和转运体两种功能模式，有强烈迹象表明质子与渗透过程耦合。我们结合分子动力学模拟、量子力学计算和pK计算，来计算FNT完整渗透循环的能量学。我们发现，阴离子本身无法穿过FNT孔。相反，阴离子结合到孔中在能量上与位于中心的组氨酸的质子化耦合。反过来，组氨酸可以使渗透的阴离子质子化，从而使其释放。这种机制可以适应FNTs之间的功能多样性，因为它可以促进底物的输出和输入，无论是否有质子共转运。该机制排除了通过Grotthuss机制的质子泄漏，并解释了对弱酸的选择性。
