Elucidating the Binding Modes of Small Molecules That Modulate the Aggregation Propensity of Hiapp
Michelle Garcia, Dartmouth College
The formation of Human IAPP (hIAPP or amylin) amyloid deposits in pancreatic beta-cells is linked to the pathogenesis of Type II Diabetes (T2D). Small molecules that inhibit or accelerate the aggregation of amylin have been discovered, but no structural or mechanistic rationale exists to explain their binding mechanisms or their effects on amylin aggregation pathways. Here, we utilize all-atom molecular dynamics computer simulations to elucidate atomically detailed binding mechanisms of an amylin aggregation inhibitor (YX-I-1) and accelerator (YX-A-1) binding to monomers of wild-type (WT) hIAPP and the natural S20G hIAPP variant that correlates with early-onset T2D. We observe that S20G mutation shifts the population towards increased intramolecular contacts and beta-sheet fractions compared to WT, suggesting different accessible conformations for binding. The inhibitor has substantially higher affinity to WT hIAPP compared to the accelerator, consistent with previous measurements from solution NMR spectroscopy. We dissect the intermolecular interactions that stabilize binding of each molecule to WT and the S20G amylin variant and quantify ligand binding changes from monomer solution ensembles relative to apo simulations. We observe that in all bound ensembles, distinct fragments of the inhibitor and accelerator are enfolded upon binding while other fragments remain solvent exposed. We hypothesize that different molecular moieties may confer binding affinity to monomeric species while exposed moieties may affect rates of intermolecular association into higher order species.