Model analysis of electrostatic interactions of ATP-IDE interactions by quantum mechanics/molecular mechanics (QM/MM) calculation and molecular dynamic (MD) simulations : A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy at Lincoln University

Abstract

The insulin-degrading enzyme (IDE) plays a significant role in the degradation of the amyloid beta (Aβ), a peptide found in regions of the brain of patients with early Alzheimer’s disease (AD). Adenosine triphosphate (ATP) allosterically regulates the Aβ-degrading activity of IDE. Electrostatic interactions between ATP-IDE including thermostabilities/flexibilities of IDE residues, at the allosteric site of IDE, are essential for drug design. These electrostatic interactions and the thermostabilities/flexibilities of IDE residues at the ATP-binding domain have not yet been systematically understood. The present study elucidates the electrostatic interactions of ATP-IDE interactions and the thermostabilities/flexibilities of the IDE residues. Computational modelling based on (QM/MM) calculation method and molecular dynamic (MD) simulations may offer great opportunities to understand biological interactions. In this study, we apply QM/MM to the proposed computational model for exploring the electrostatic interactions of ATP and IDE. Molecular dynamic (MD) simulations are performed at different heat-shock temperatures for identifying thermostable and flexible residues of IDE at ATP-binding domain. The proposed computational model contains five main procedures, including initial structure preparation, molecular docking, molecular mechanics (MM) equilibration, QM/MM minimisation and MD simulation. Since the allosteric effects resulting from the interactions of Aβ peptide can influence the conformational change at ATP-binding domain, we create two systems for comparing the difference between system with and without the interaction of Aβ peptide. Subsequently, the binding affinity of the electrostatic interactions of ATP-IDE interactions can be identified after performing QM/MM minimisations. Furthermore, we perform the MD simulations to explore the thermostabilities/flexibilities of the IDE residues at the different temperatures (300K, 321.15 K and 315.15 K), which 321.15 K and 315.15 K are the temperatures induce a heat-shock response (a protective mechanism) of IDE. The proposed computational model predicts QM/MM minimised structures. Subsequently, it reveals the IDE residues with high binding affinity (LYS530 and ASP385). Considering root-mean-square-fluctuation (RMSF) values during the MD simulations at the heat-shock temperatures, it 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 within the IDE which has important implications for pharmacological drug design. The proposed computational model may facilitate the development of allosteric IDE activators/inhibitors which mimic ATP interactions.