Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

da Cruz, Carlos H.  B.; Seabra, Gustavo

doi:10.1021/ci400695m

Title: Molecular Dynamics Simulations Reveal a Novel Mechanism for ATP Inhibition of Insulin Degrading Enzyme

Journal Article · Tue Apr 22 00:00:00 EDT 2014 · Journal of Chemical Information and Modeling

DOI:https://doi.org/10.1021/ci400695m· OSTI ID:1565148

da Cruz, Carlos H. B. ^[1]; Seabra, Gustavo ^[2]

Univ. Federal de Pernambuco (Brazil). Dept. de Química Fundamental
Univ. Federal de Pernambuco (Brazil). Dept. de Química Fundamental

Regulation of brain levels of the Amyloid-β 42 (Aβ42) polypeptide by IDE has recently been linked with possible routes for new therapies against Alzheimer’s disease (AD). One important aspect is the regulatory mechanism of IDE by ATP, which is an IDE activator in degrading small peptides and an inhibitor in degrading larger peptides, such as Aβ42. This relationship was investigated in this study. We present molecular dynamics simulations of Aβ42 complexed with IDE, in the absence or presence of either ATP or excess Na⁺ and Cl^– ions. Results suggest a previously unreported inhibition mechanism that depends on charge-induced structural modifications in the active site and interactions simultaneously involving ATP, Aβ42, and IDE. Such interactions exist only when both ATP and Aβ42 are simultaneously present in the catalytic chamber. This mechanism results in allosteric, noncompetitive inhibition with apparent decrease of substrate affinity, in accordance with experiment.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1565148

Journal Information:: Journal of Chemical Information and Modeling, Vol. 54, Issue 5; ISSN 1549-9596

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 13 works

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