title: QM/MM simulations of amyloid-β 42 degradation by IDE in the presence and absence of ATP.
abstract: The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-β 42 (Aβ42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Aβ42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 ± 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times.
authors.affiliation: Departamento de Química Fundamental, Universidade Federal de Pernambuco , Av. Jornalista Aníbal Fernandes, s/n, Cidade Universitária, Recife-PE, Brazil , 50.740-560.
authors.forename: Carlos H B
authors.initials: CH
authors.lastname: da Cruz
authors.forename: G M
authors.initials: GM
authors.lastname: Seabra
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D007339:Insulysin / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011789:Quantum Theory
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D007339:Insulysin