On electrostatic interactions of adenosine triphosphate–insulin‐degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics

The insulin-degrading enzyme (IDE) plays a significant role in the degradation of the amyloid beta (Aβ), a peptide found in the brain regions of the patients with early Alzheimer's disease. Adenosine triphosphate (ATP) allosterically regulates the Aβ-degrading activity of IDE. The present study investigates the electrostatic interactions between ATP-IDE at the allosteric site of IDE, including thermostabilities/flexibilities of IDE residues, which have not yet been explored systematically. This study applies the quantum mechanics/molecular mechanics (QM/MM) to the proposed computational model for exploring electrostatic interactions between ATP and IDE. Molecular dynamic (MD) simulations are performed at different temperatures for identifying flexible and thermostable residues of IDE. The proposed computational model predicts QM/MM energy-minimised structures providing the IDE residues (Lys530 and Asp385) with high binding affinities. Considering root mean square fluctuation values during the MD simulations at 300.00 K including heat-shock temperatures (321.15 K and 315.15 K) indicates that Lys530 and Asp385 are also the thermostable residues of IDE, whereas Ser576 and Lys858 have high flexibilities with compromised thermostabilities. The present study sheds light on the phenomenon of biological recognition and interactions at the ATP-binding domain, which may have important implications for pharmacological drug design. The proposed computational model may facilitate the development of allosteric IDE activators/inhibitors, which mimic ATP interactions.