Calcium ions are known to modulate amyloid peptide aggregation on neuronal membrane surfaces, influencing disease progression in neurodegenerative disorders such as Alzheimer's, Parkinson’s, and Huntington’s. Despite this, the underlying molecular mechanisms governing calcium’s effects remain poorly understood. To address this knowledge gap, we employed coarse-grained molecular dynamics simulations to investigate the aggregation of amyloid-β’s K16LVFFAE22 fragment (Aβ16−22) on a mixed lipid bilayer comprising 30% POPS and 70% POPC lipids. We find that calcium ions rapidly condense POPS lipids around the peptides, restricting peptide mobility on the bilayer surface. This calcium-mediated lipid reorganization delays oligomer growth compared to calcium-free conditions. Over extended timescales, peptide aggregates evolve into ordered structures encapsulated by POPS lipids stabilized by PS-Ca 2+ -PS ionic bridges. Calcium ions reduce the area per lipid of POPS molecules surrounding peptide aggregates, sterically hindering further peptide addition to these aggregates. This leads to the stabilization of smaller, more rigid peptide assemblies in calcium-rich environments. In contrast, in the absence of calcium ions, aggregates dynamically break apart and reassemble to form larger aggregates. These findings align with experimental observation that calcium ions favor the formation of smaller amyloid aggregates. Together, our results highlight that calcium restricts peptide mobility and stabilizes smaller, rigid aggregates through POPS lipid condensation and ionic bridging. This mechanism provides molecular-level insights for understanding calcium’s role in amyloid aggregation and neurodegeneration, potentially informing therapeutic intervention strategies.
Jain et al. (Sun,) studied this question.