Insulin modulates the free energy landscape of insulin degrading enzyme as it transitions between closed and open states

Insulin Degrading Enzyme (IDE) is an enzyme that has been linked to type-2 diabetes mellitus as it degrades molecules responsible for controlling blood glucose level including insulin, amylin, and glucagon. It is also responsible for degrading amyloid beta, the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. IDE transitions between open and closed conformations in the process of degrading insulin, however the exact mechanism of these conformational changes is not fully understood. We ran two sets of molecular dynamics simulations following the string method with swarms of trajectories and bias exchange umbrella sampling protocols in order to produce a physical pathway for IDE transitioning between closed and open states and to investigate the effect of insulin on this conformational change. We observed a free energy barrier between the closed and open conformations of the insulin-free system that could be attributed to the breakage of the ASP426-LYS571, ASP82-LYS243 and GLU428-LYS899 salt bridges that connect the D2 and D3 domains of IDE. The insulin-bound system had a considerable change in the shape of the free energy landscape where the transition energy barrier was lowered. Additionally, insulin stabilized the open state conformation of IDE by lowering its free energy. We observed the formation of three salt bridges in the insulin-bound system that were not present in the insulin-free system. Dynamical Network and Principal Component Analyses of our trajectories provided intuition as to how the different clusters of atoms within IDE interact with each other and with insulin, and how these interactions contribute to the overall conformational change. In particular, the first domain of IDE (shown experimentally to be important in insulin degradation) was divided into two dynamical subdomains.