Elucidation of Interactions of Alzheimer Amyloid β Peptides (Aβ40 and Aβ42) with Insulin Degrading Enzyme: A Molecular Dynamics Study

In this study, interactions of the two full-length Alzheimer amyloid beta peptides (A beta 40 and A beta 42) 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 A beta 40 and Asp1-Glu3 and Lys16-Glu22 of A beta 42) mutated forms of IDE and NMR structures of the full-length A beta 40 and A beta 42 have been used to build the starting structures for these simulations. The most representative structures derived from the A beta 40-IDE and A beta 42-IDE simulations accurately reproduced the locations of the active site Zn2+ 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, pi-pi, CH-pi, and NH-pi interactions. In comparison to A beta 40, A beta 42 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 beta-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 A beta peptides by IDE.