Abstract
The missense mutation S20G in the human islet amyloid polypeptide (hIAPP) is supposed to be associated with the early onset of type II diabetes (T2DM) in Asian population. How such a single-point mutation induces variation of the conformation distribution and the amyloidogenic properties of hIAPP is still unknown. We studied the conformational ensembles of hIAPP segment 15-27 in both wild type and the S20G mutant type by performing extensive replica exchange molecular dynamics simulations in explicit solvent model. Our results reveal that the residue G20 initiates a turnlike structure in the neighborhood, facilitating the formation of long-ranged contacts. Moreover, we find that the point mutation favors protofibril model of full length hIAPP suggested recently based on experimental measurements. Such a conformational preorganization will decrease the entropy cost during the process of peptide self-assembly, which is a possible explanation of the faster fibrillation of hIAPP S20G mutant than that of the wild type found by experiments.
Published Version
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