In this study, interactions of the two full-length Alzheimer amyloid β peptides (Aβ40 and Aβ42) with the fully active form of insulin degrading enzyme (IDE) through unrestrained, all-atom MD simulations have been investigated. This enzyme is a Zn-containing metallopeptidase that catalyzes the degradation of the monomeric forms of these peptides, and this process is critical for preventing the progression of Alzheimer s disease (AD). The available X-ray structures of the free and small fragment-bound (Asp1?Glu3 and Lys16?Asp23 of Aβ40 and Asp1?Glu3 and Lys16?Glu22 of Aβ42) mutated forms of IDE and NMR structures of the full-length Aβ40 and Aβ42 have been used to build the starting structures for these simulations. The most representative structures derived from the Aβ40?IDE and Aβ42?IDE simulations accurately reproduced the locations of the active site Zn 2+ metal and small fragments of the substrates and their interactions with the enzyme from the X-ray structures. The remaining fragments of both the substrates were found to interact with IDE through several hydrogen bonding, π?π, CH?π, and NH?π interactions. In comparison to Aβ40, Aβ42 is more flexible and interacts through a smaller number (17?22) of hydrogen bonds in the catalytic chamber of IDE. Both the substrates adopted more β-sheet character in the IDE environment, an observation that is in line with experiments. Their structural characteristics inside IDE are significantly different than the ones observed in aqueous solution. The atomistic level details provided by these simulations can help in the elucidation of binding and degrading mechanisms of the Aβ peptides by IDE.
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