Release of Entropic Spring Reveals Conformational Coupling Mechanism in the ABC Transporter BtuCD-F.
Release of Entropic Spring Reveals Conformational Coupling Mechanism in the ABC Transporter BtuCD-F.
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DOI：
10.1016/j.bpj.2016.04.027
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发表时间：
2016-06
影响因子：
3.4
通讯作者：
Marten Prieß;Lars V. Schäfer
中科院分区：
文献类型：
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作者：
Marten Prieß;Lars V. Schäfer
ATP结合盒（ABC）转运蛋白的底物转运涉及核苷酸结合结构域（NBD）中ATP结合和水解与跨膜结构域构象变化的偶联。我们用分子动力学模拟研究了ABC转运蛋白BtuCD-F的构象偶联的原子水平机制，该转运蛋白通过大肠杆菌的内膜输入维生素B12。我们的模拟显示了如何在NBD二聚体界面的工程二硫键减少构象波动，因此构型熵。因此，二硫键处于显著的机械应力下。释放这种熵弹簧，就像野生型转运蛋白的情况一样，结合分析单个残基之间的成对力，解开了耦合机制。力从NBD经由偶联螺旋传播到跨膜结构域的所鉴定的途径沿着由高度保守的残基组成，强调了它们的功能相关性。这项研究不仅揭示了BtuCD-F中构象偶联的细节，还为其他长程构象偶联提供了一种有前途的方法，例如，在ABC出口商或其他ATP驱动的分子机器中。
Substrate translocation by ATP-binding cassette (ABC) transporters involves coupling of ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) to conformational changes in the transmembrane domains. We used molecular dynamics simulations to investigate the atomic-level mechanism of conformational coupling in the ABC transporter BtuCD-F, which imports vitamin B12 across the inner membrane ofEscherichia coli. Our simulations show how an engineered disulfide bond across the NBD dimer interface reduces conformational fluctuations and hence configurational entropy. As a result, the disulfide bond is under substantial mechanical stress. Releasing this entropic spring, as is the case in the wild-type transporter, combined with analyzing the pairwise forces between individual residues, unravels the coupling mechanism. The identified pathways along which force is propagated from the NBDs via the coupling helix to the transmembrane domains are composed of highly conserved residues, underlining their functional relevance. This study not only reveals the details of conformational coupling in BtuCD-F, it also provides a promising approach to other long-range conformational couplings, e.g., in ABC exporters or other ATP-driven molecular machines.