Investigating the pH influence on insulin fibril stability: Molecular dynamics insights.

The research highlights the impact of pH on the structural stability of insulin amyloid fibrils, linked to clinical complications such as insulin-derived amyloidosis and potential insulin resistance. Using molecular dynamics (MD) simulations, we demonstrate that at neutral pH (pH 7), deprotonated glutamate residues create electrostatic repulsion within the fibril core. This reduces inter-protomer hydrogen bonding and leads to partial destabilization. In contrast, at acidic pH (pH 2), protonation of acidic residues diminishes repulsion, facilitating tighter packing and a more organized hydrogen-bond network. Further analyses, including hydration shell characterization and principal component analysis (PCA), underscore structural differences between fibrils under different pH conditions. At pH 7, the fibrils exhibit a more hydrated shell and greater collective motions, revealing reduced compactness and stability. Residues such as Leu, Glu, and Gln are crucial for fibril stability, with their hydrogen bonding participation notably reduced at neutral pH. These findings provide critical insights into the molecular mechanisms underlying the pH-dependent destabilization of insulin fibrils. Such a mechanistic understanding holds significant potential for guiding the development of therapeutic strategies aimed at preventing fibril formation or promoting controlled fibril disassembly. These advancements could help address the challenges posed by insulin-derived amyloidosis, thereby improving clinical outcomes for patients requiring recurrent insulin therapy.