Molecular Mechanism of the Inhibition and Remodeling of Human Islet Amyloid Polypeptide (hIAPP1-37) Oligomer by Resveratrol from Molecular Dynamics Simulation

Natural polyphenols are one of the most actively investigated categories of amyloid inhibitors, and resveratrol has recently been reported to inhibit and remodel the human islet amyloid polypeptide (hIAPP) oligomers and fibrils. However, the exact mechanism of its action is still unknown, especially for the full-length hIAPP(1-37). To this end, we performed all-atom molecular dynamics simulations for hIAPP(1-37) pentamer with and without resveratrol. The obtained results show that the binding of resveratrol is able to cause remarkable conformational changes of hIAPP(1-37) pentamer, in terms of secondary structures, order degree, and morphology. By clustering analysis, two possible binding sites of resveratrol on the hIAPP(1-37) pentamer were found, located at the grooves of the top and bottom surfaces of beta-sheet layer, respectively. After the binding free energy calculation and residue energy decomposition, it can be concluded that the bottom site is the more possible one, and that the nonpolar interactions act as the driving force for the binding of hIAPP(1-37) to resveratrol. In addition, Arg11 is the most important residue for the binding of resveratrol. The full understanding of inhibitory mechanism of resveratrol on the hIAPP(1-37) oligomer, and the identification of its binding sites on this protein are helpful for the future design and discovery of new amyloid inhibitors.