The multidrug resistance (MDR) system actively pumps antibiotics out of cells causing serious health problems. During the pumping, AcrB (one of the key components of MDR) undergoes a series of large-scale and proton-motive conformational changes. Capturing the conformational changes through all-atom simulations is challenging. Here, we implement a hybrid coarse-grained force field to investigate the conformational changes of AcrB in the porter domain under different protonation states of Asp407/Asp408 in the trans-membrane domain. Our results show that protonation of Asp408 in monomer III (extrusion) stabilizes the asymmetric structure of AcrB; deprotonation of Asp408 induces clear opening of the entrance and closing of the exit leading to the transition from extrusion to access state. The structural changes in the porter domain of AcrB are strongly coupled with the proton translocation stoichiometry in the trans-membrane domain. Moreover, our simulations support the postulation that AcrB should adopt the symmetric resting state in a substrate-free situation.

中文翻译：

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多药外排转运蛋白AcrB中构象变化的粗粒模拟

多药耐药性（MDR）系统会主动将抗生素泵出细胞，从而导致严重的健康问题。在泵送过程中，AcrB（MDR的关键成分之一）经历了一系列大规模的质子动力构象变化。通过全原子模拟捕获构象变化具有挑战性。在这里，我们实现了一个混合的粗粒度力场，以研究在跨膜结构域中Asp407 / Asp408的不同质子化状态下，搬运结构域中AcrB的构象变化。我们的结果表明，单体III中的Asp408的质子化（挤压）稳定了AcrB的不对称结构。Asp408的去质子化导致入口的明显打开和出口的闭合，从而导致从挤压状态过渡到进入状态。AcrB的波特结构域中的结构变化与跨膜结构域中的质子易位化学计量学紧密相关。此外，我们的仿真支持AcrB在无基材情况下应采用对称静止状态的假设。