Atomistic molecular dynamics simulations of ATP‐binding cassette transporters

Abstract

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.1247This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics