title: ATP Hydrolysis Mechanism in a Maltose Transporter Explored by QM/MM Metadynamics Simulation.
abstract: Translocation of substrates across the cell membrane by adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporters depends on the energy provided by ATP hydrolysis within the nucleotide-binding domains (NBDs). However, the detailed mechanism remains unclear. In this study, we focused on maltose transporter NBDs (MalK2) and performed a quantum mechanical/molecular mechanical (QM/MM) well-tempered metadynamics simulation to address this issue. We explored the free-energy profile along an assigned collective variable. As a result, it was determined that the activation free energy is approximately 10.5 kcal/mol, and the reaction released approximately 3.8 kcal/mol of free energy, indicating that the reaction of interest is a one-step exothermic reaction. The dissociation of the ATP γ-phosphate seems to be the rate-limiting step, which supports the so-called dissociative model. Moreover, Glu159, located in the Walker B motif, acts as a base to abstract the proton from the lytic water, but is not the catalytic base, which corresponds to an atypical general base catalysis model. We also observed two interesting proton transfers: transfer from the His192 ε-position nitrogen to the dissociated inorganic phosphate, Pi, and transfer from the Lys42 side chain to adenosine 5'-diphosphate β-phosphate. These proton transfers would stabilize the posthydrolysis state. Our study provides significant insight into the ATP hydrolysis mechanism in MalK2from a dynamical viewpoint, and this insight would be applicable to other ABC transporters.
authors.affiliation: Center for Biological Resources and Informatics, Tokyo Institute of Technology , 4259-B-62, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Center for Biological Resources and Informatics, Tokyo Institute of Technology , 4259-B-62, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Furuta
authors.affiliation: Center for Biological Resources and Informatics, Tokyo Institute of Technology , 4259-B-62, Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakurai
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry*; D006868:Hydrolysis; D008320:Maltose / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory
chemical_list: D018528:ATP-Binding Cassette Transporters; D008320:Maltose; D000255:Adenosine Triphosphate