Computational Insights into Dopamine-Mediated Conformational Transitions of Aβ Aggregates in Alzheimer's Disease.

Alzheimer's disease (AD) is a looming neurological pandemic that affects over 57 million individuals globally and poses a challenge for the healthcare system due to its complex etiology and the fact that it remains incurable despite extensive research efforts. Among the various pathological contributors, dopaminergic dysfunction has emerged as a critical factor implicated in AD, causing apathy, depression, cognitive decline, and hallucinations, which significantly exacerbate disease progression and patient morbidity. Despite dopamine's multifarious role in modulating β-amyloid (Aβ) aggregation and in the pathogenesis of AD, the precise molecular interaction mechanism remains poorly understood. In this study, we employ molecular dynamics (MD) simulations to elucidate dopamine's conformation-specific interactions with Aβ across four hierarchical aggregation states: monomer, trimer, pentamer, and a nine-chain fibrillar assembly. This computational approach reveals that dopamine strongly perturbs the monomeric and trimeric forms, disrupting β-sheet structures and promoting α-helix formation. At the pentameric state, dopamine induces partial α-helix formation while weakening interchain hydrogen bonds and salt bridge interactions, indicating intermediate destabilization. In sharp divergence, the mature fibril exhibits structural rigidity with minimal conformational alteration and no disruption in the β-sheet content. These findings provide an advanced understanding of the conformation-dependent modulation mechanism whereby dopamine selectively interferes with the early nucleation phase rather than fibril elongation; also dopamine exhibits the most pronounced β-sheet disruption in monomers but shows progressively diminished efficacy in higher-order oligomeric and fibrillar assemblies. This selective interaction landscape highlights dopamine's potential as a modulator of early amyloidogenic events and offers novel insights for understanding dopamine-based therapeutic strategies for AD.