Deciphering the Inhibitory Mechanism of hIAPP-Derived Fragment Peptide Against hIAPP Aggregation in Type 2 Diabetes**

The aggregates of human islet amyloid polypeptide (hIAPP or amylin) are well-known causative agents of type 2 diabetes (T2D). Previous experimental studies reported that hexapeptide ANFLVH inhibited IAPP aggregation and completely prevented IAPP-mediated toxicity. However, the underlying inhibitory mechanism at the atomic level is not completely understood. In this regard, the molecular mechanism of the inhibition of hIAPP aggregation in the presence of ANFLVH has been elucidated by molecular dynamics (MD) simulations in the present study. MD simulation analysis highlighted that ANFLVH prevented the conformational transition of hIAPP by stabilizing the native helical conformation. The binding free energy analysis by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method highlighted favourable binding (Delta G(binding)=-49.90 +/- 0.67 kcal/mol) of ANFLVH with hIAPP and depicted a significant contribution of the van der Waals interaction term (Delta E-vdW=-46.33 +/- 0.32 kcal/mol) in the stability of the hIAPP-ANFLVH complex. The per-residue binding free energy highlighted that ANFLVH strongly interacted with His18 of hIAPP, which has been reported as a key residue in mediating the hIAPP self-assembly process. The present work sheds light on the inhibitory mechanism of ANFLVH against hIAPP aggregation at the atomic level. The study will guide the rational design and development of therapeutic candidates against hIAPP aggregation in T2D.