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WIREs Comput Mol Sci
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Atomistic molecular dynamics simulations of ATP‐binding cassette transporters

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Membrane transporters are transmembrane proteins that facilitate the translocation of a broad range of substrates across biological membranes. These proteins play a pivotal role in drug absorption, distribution, metabolism, and excretion, as well as drug resistance in cancer and pathogenic microorganisms. Moreover, some of them are appealing therapeutic targets. Computational methods, especially atomistic molecular dynamics (MD) simulations, are now increasingly employed to investigate the structural and thermodynamic properties of these proteins. Computer simulations at an atomic resolution help to decipher the underlying mechanisms of these transporters and provide valuable insights into structure‐based drug discovery. Here, recent advances of the applications of MD simulations on the studies of a major class of membrane transporters, the ATP‐binding cassette (ABC) superfamily, are reviewed. The studies surveyed here are mainly focused on the working mechanisms of ABC transporters, including binding of substrates, conformational coupling between nucleotide‐binding domains (NBDs) and transmembrane domains, dynamics of NBDs, and global movement of complete transporters. In addition, structural and functional changes upon mutations are also discussed in some medically relevant cases. WIREs Comput Mol Sci 2016, 6:255–265. doi: 10.1002/wcms.1247 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics
Structural organization of the heterotetrameric ECF‐type ABC transporter.
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Typical architecture of the NBDs of ABC transporters. The conserved motifs are highlighted and colored as follows: Walker A or P‐loop, pink; Q‐loop, green; Signature or C‐loop, blue; Walker B, orange; Switch or H‐loop, red.
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Overall structures of four types of full‐length ABC transporters. From left to right, there are type I importers exemplified by the MalFGK2‐MBP complex (PDB code: 2R6G), type II importers exemplified by the BtuCD‐F complex (PDB code: 2QI9), exporters exemplified by Sav1866 (PDB code: 2HYD), and ECF‐type importers exemplified by the hydroxymethyl pyrimidine transporter (PDB code: 4HZU). The NBDs and TMDs are colored pink and blue, respectively. For type I and II importers, the additional SBPs are highlighted in orange.
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ATP hydrolysis reaction catalyzed by ATPase, where Pi is short for inorganic phosphate.
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Schematic representation of the proposed alternating access model for a working transporter. The transporter and substrate are shown by blue squares and red circles, respectively.
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Schematic representation of three categories of membrane transporters: primary active transporter (depicted by blue square and green ellipse), secondary active transporter (depicted by pink square), and facilitator (depicted by orange square). The transported substrates are represented by gray and blue circles with the directions of movement indicated by the arrows.
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