Exploring the Implications of Vitamin B ₁₂ Conjugation to Insulin on Insulin Receptor Binding

The dynamic behavior of insulin in solution and its binding geometry with the insulin receptor (IR) have been the focus of experimental and computational studies. We investigated how the structure of an orally deliverable insulin changes in solution after vitamin B 12 conjugation and its effect on IR binding capacity. In vitro immunoelectron microscopy confirms conjugate activity, IR binding, and cellular uptake. magnified image We recently reported a vitamin B 12 (B 12 ) based insulin conjugate that produced significantly decreased blood glucose levels in diabetic STZ‐rat models. The results of this study posed a fundamental question, namely what implications does B 12 conjugation have on insulin's interaction with the insulin receptor (IR)? To explore this question we used a combination of molecular dynamics simulations and immunoelectron microscopy, and the results are described herein. This investigation demonstrates that chemical modification of insulin by linking relatively large pendant groups does not inherently interfere with IR recognition. Furthermore, given that we have previously demonstrated a significant drop in blood glucose concentration following the oral administration of the B 12 –insulin bioconjugate used in this work, it is reasonable to conclude that the IR recognition described herein is associated with maintenance of biological activity for insulin. This outcome offers significant research scope for chemical modification of insulin with the purpose of improving oral‐uptake efficiency.