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- W2792297977 abstract "Dopamine β-hydroxylase (DBH) is an enzyme that catalyzes the conversion of dopamine into norepinephrine. An imbalance of these neurotransmitters can lead to many neurological and psychiatric disorders. A key step in the mechanism involves an electron transfer between two copper centers. Based on the structure of other hydroxylases, mechanisms invoking organized water networks have been proposed, where the electron is transferred over a distance greater than 10 Å. X-ray crystallography has recently shown that DBH is a homodimer in which the distance between the two copper centers can span both short (5 Å) and long (15 Å) distances. Our hypothesis is that the protein can switch between open and closed states at a rate that is compatible with catalysis. In the closed state, the short-distance between the two-copper center is exploited to transfer the electron, whereas the open state facilitates substrate binding and release. To test this hypothesis, we used molecular dynamic simulations. We have developed the parameters necessary to describe the copper centers with the CHARMM molecular mechanics force field, reconstructed regions missing in the structure, and refined the structure to better account for disulfide bond formation and hydrogen bond networks. Finally, we used free energy perturbations of Na+, K+, Mg2+, and Ca2+ to determine the most stable ion configuration in the putative ion binding site in the DOMON domain. The results from our initial computer simulations are compatible with the proposed hypothesis. If our hypothesis stands further testing, it would provide an alternative mechanism that can explain the electron transfer between the copper centers without the intervention of organized water networks." @default.
- W2792297977 created "2018-03-29" @default.
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- W2792297977 date "2018-02-01" @default.
- W2792297977 modified "2023-10-16" @default.
- W2792297977 title "Conformational Dynamics of Dopamine β-Hydroxylase by Computer Simulations" @default.
- W2792297977 doi "https://doi.org/10.1016/j.bpj.2017.11.321" @default.
- W2792297977 hasPublicationYear "2018" @default.
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