Deciphering the impact of F23L mutation on the aggregation propensity of human islet amyloid polypeptide using molecular simulations

The self-aggregation of 37-residue human islet amyloid polypeptide (hIAPP) into n- sheet rich oligomers and amyloid fibrils contributes to the loss of pancreatic n- cell mass in type 2 diabetes (T2D). A previous study highlighted that the F23L mutation in the amyloidogenic core (Ser20-Ser29) of hIAPP slows down its self- aggregation by a factor of 2.6. However, the underlying molecular mechanism behind slower aggregation and reduced cytotoxicity of hIAPP on F23L mutation remains obscure. Thus, the structural and conformational changes in F23L-hIAPP that lead to slower aggregation and lower cytotoxicity were examined by molecular dynamics (MD) simulations. The MD simulations depicted that F23L mutation marginally increases the helical content from 10.20 f 1.94 to 11.50 f 2.18 % accompanied by a noteworthy decrease in aggregation-prone n- sheet from 14.00 f 1.58 to 0.80 f 0.37 %. Notably, FEL conformations depicted a complete disappearance of n- sheet content in F23L-hIAPP as compared to 9-20 % in wt-hIAPP in agreement with the notably reduced toxicity of F23L-hIAPP aggregates against cultured INS-1 832/13 cells. Interestingly, dihedral principal component analysis (dPCA) depicted noteworthy compression in the conformational sub-space and a lower trace value of hIAPP on F23L mutation, which indicates lower conformational fluctuations in F23L-hIAPP. F23L mutation alters the conformational landscape of hIAPP dimer by lowering interchain contacts, and hydrogen bonds as well as reducing binding affinity between chains A-B of hIAPP dimer. Importantly, MD simulations illuminated the key role of Phe23 in mediating intramolecular interactions leading to aggregation-prone structures that promote hIAPP aggregation. The key insights regarding structural transitions and conformational preferences of hIAPP on F23L mutation illuminated from this work will benefit the design and optimization of potential inhibitors targeting Phe23-mediated interactions to block hIAPP aggregation in T2D.