title: Conformational Dynamics and Protein-Substrate Interaction of ABC Transporter BtuCD at the Occluded State Revealed by Molecular Dynamics Simulations.
abstract: ATP-binding cassette (ABC) transporters are ubiquitous in all three kingdoms of life and are implicated in many clinically relevant physiological processes. They couple the energy released by ATP hydrolysis to facilitate substrate translocation across cell membranes. The crystal structures of type II ABC importers have revealed their unique transmembrane domain architecture consisting of 10 transmembrane helices and their structurally conserved nucleotide-binding domains among all ABC transporters. However, molecular details of the interactions between the importers and their substrate remain largely elusive. Taking vitamin B12importer BtuCD as an exemplar of type II importers, we investigated the dynamics of its occluded state and the detailed protein-substrate interactions using molecular dynamics simulation. Our trajectories show that the importer accommodates the substrate through a nonspecific binding mode as the substrate undergoes evident vertical and tilt motions inside the translocation cavity. Extensive hydrogen bond and hydrophobic interactions were observed between the substrate and the importer; however, most of these interactions are weak, with <38% occurrence. The presence of substrate leads to enlargement of the translocation cavity, especially at its cytoplasmic end, which may activate cytoplasmic regions and probably facilitate the transportation. The perturbations caused by periplasmic binding protein and nucleotides were also investigated. The study provides deeper insight into the translocation mechanism of BtuCD.
authors.affiliation: Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University , Shanghai, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Pan
authors.affiliation: Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University , Shanghai, P. R. China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Weng
authors.affiliation: Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, and Institutes of Biomedical Sciences, Fudan University , Shanghai, P. R. China.
authors.forename: Wenning
authors.initials: W
authors.lastname: Wang
mesh_terms: D029968:Escherichia coli Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D029968:Escherichia coli Proteins