Why insulin aspart and insulin degludec exhibit distinct release mechanisms

Abstract Exploring the molecular mechanisms underlying insulin analogs is important for protein engineering to design innovative drug proteins. Insulin aspart (IAsp) and insulin degludec (IDeg) are representative examples of insulin analogs with distinct release profiles synthesized by targeted mutagenesis in protein engineering. Despite their importance in diabetes treatment, there remains a gap in our understanding of the molecular basis for their differential release mechanisms. In this study, ordinary molecular dynamics simulation and steered molecular dynamics are utilized to investigate the structural stability, solubility analysis, and monomer interactions of these insulins, with the aim to explain the mesoscale differences between the two insulin release mechanisms. Simulation findings have further been validated through experimental verification, shedding light on the intricate mechanisms underlying insulin release and providing valuable insights into pharmaceutical implications and potential advancements in the design of insulin therapy.