Rosmarinic Acid Inhibits β-Sheet and β-Hairpin Formation in Human Islet Amyloid Polypeptide Dimers by Stabilizing Localized C-Terminal Motifs: An REMD Study

Abstract

The misfolding of human islet amyloid polypeptide (hIAPP) into soluble oligomers is a primary pathological event in type 2 diabetes, with the early dimerization process representing a critical pharmacological target. Here, we investigate the molecular mechanism by which rosmarinic acid (RA) counteracts full-length hIAPP self-association through replica-exchange molecular dynamics. Our results show that RA drastically suppresses overall β-sheet propensities and truncates extended, aggregation-competent β-strands, lowering the sampled population of ordered β-hairpin-like motifs associated with amyloidogenic hIAPP conformations. Instead of forming compact structures, the hIAPP dimer is diverted toward disordered, hyper-solvated topologies. This conformational remodeling is driven by spatially heterogeneous thermodynamic perturbations that disrupt native interpeptide contacts and transfer structured motifs into localized turn and bend structures at the C-terminus. Energetically, RA outcompetes peptide–peptide interactions via a multimodal strategy, preferentially anchoring to the hIAPP N-terminus through residues K1 and R11 while simultaneously engaging the hydrophobic core via π–π stacking. Notably, this robust noncovalent occupation of key amyloidogenic regions occurs spontaneously in the simulations, offering an atomistic clue for modulating early hIAPP self-association. These structural and energetic insights clarify how RA interacts with transient hIAPP dimer ensembles, providing a defined biophysical framework for the rational design of amyloid inhibitors.