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

In 2019, official death certificates reported that there were 121,499 deaths due to Alzheimer's disease (AD). AD is the sixth-leading cause of death in the United States. By 2060, this number could rise to 13.8 million unless there are medical advancements to prevent, slow down, or cure AD.

To prevent or slow down the AD, therapeutic and pharmacological intervention must be performed in the early stage of AD. Many studies have identified that Amyloid beta (Aβ) peptides contribute to AD. In the early stage of AD, one of the molecular processes involved is the impairment of insulin-degrading enzyme (IDE). Normally, IDE is responsible for breaking down Aβ peptides (Aβ clearance). In the early stage of AD, IDE activities can be disrupted. This leads to Aβ accumulation, which plays a role to accelerate AD progression.

Adenosine triphosphate (ATP) acts as a negative regulator of IDE in Aβ clearance. The interactions of ATP can cause a conformational change of IDE, which reduce the activities of Aβ clearance. To inhibit the ATP interactions, drug design for pharmacological intervention for AD requires the understanding of ATP-IDE interactions at deep levels – molecular and quantum levels.

Recently, researchers from New Zealand published an article, titled “On electrostatic interactions of adenosine triphosphate–insulin‐degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics” in Quantitative Biology. This study has successfully adopted the quantum mechanics/molecular mechanics (QM/MM) calculation method to explore the biological interaction between protein targets and the drug agents. Also, molecular dynamic (MD) simulation method has been applied to the computational models to explore the stabilities and flexibilities of protein targets at unstable temperatures. These are essential to the pharmacological drug design.

The study also proposed a computational model used hybrid of QM/MM and MD to explore between ATP and IDE at molecular and quantum levels (Figure 1). The authors anticipate that the proposed model provides the crucial information facilitating the development of IDE inhibitors against ATP interaction. According to the experimental results, the details of ATP-IDE interactions at molecular and quantum levels are revealed.