Insulin Aspart Dimer Dissociation in Water

Abstract

The insulin hormone stored in hexameric form, and dissociates to dimeric form and finally to the active monomeric form. When insulin secretion is impaired whereby affecting various metabolic processes, as a final response insulin analogs are subcutaneously injected before meals to facilitate glucose metabolism. Depending on the molecular details, analogs are rapid or slow acting based on the dissociation rate of dimer to monomer. Insulin Aspart is a recombinant human insulin analog, acting faster than regular human insulin. Despite its practical and elementary importance, the process of insulin aspart dimer dissociation is relatively unknown. Here, we combined molecular dynamics simulations and umbrella sampling to characterize the energetic and structural features of dissociation of insulin aspart dimer. Like previous studies on human insulin (another well studied analog), insulin aspart can also display wide spectrum of pathways for dimer dissociation: from dissociation happening without major change in monomer structure to dissociation that is coupled with unfolding of protein. Additionally, water plays a vital role in the dissociation of the insulin aspart by stabilizing the monomers in the dissociated state. Our study shows the molecular details, such as the variation in the structural and orientation and conformational changes along the minimum energy pathways in the process of dissociation of insulin aspart dimer.