Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Brussels, Belgium.
UGSF-Unité de glycobiologie structurale et fonctionnelle, University Lille, CNRS, UMR 8576, Lille, France.
Sci Rep. 2018 Oct 23;8(1):15607. doi: 10.1038/s41598-018-33963-1.
The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg from Arg of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg. Our data suggests that the binding of Arg promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg and an anion-π interaction involving Glu208.
精氨酸-胍丁胺反向转运体（AdiC）是肠道细菌开发的一种酸抗性系统的组成部分，用于抵抗胃酸。为了避免中性质子反向转运，单价形式的精氨酸，在酸性条件下其丰度与二价形式相当，应该被 AdiC 选择性结合以运输到细胞质中。在这项研究中，我们通过使用分子动力学模拟与分子和量子力学计算相结合的方法，研究了两种形式（除了二价胍丁胺外）的结合情况，从而揭示了 AdiC 区分 Arg 和 Arg 的机制。我们表明，AdiC 确实优先结合 Arg。二价化合物的结合较弱主要是由于它们比 Arg 更容易保持水合状态。我们的数据表明，Arg 的结合促进了门控残基 Glu208 的去质子化，这反过来又增强了它与 AdiC 的相互作用，导致 Arg 在结合位点的停留时间更长。尽管配体的总电荷似乎是区分过程中的决定因素，但与结合位点的另一个门控残基 Trp293 形成的两个局部相互作用也有助于选择机制：Arg 的胍基与阳离子-π 相互作用和涉及 Glu208 的阴离子-π 相互作用。
