Theoretical Chemistry of Condensation Systems 2026

Abstract

Protein aggregation is strongly influenced by electrostatic interactions, which depend on the protonation state of titratable groups and their local environment. In this work, I present a residue-resolved analysis of insulin fibrils using constant pH molecular dynamics (CpHMD) to investigate how protonation equilibria couple to fibril stabiity and mechanical response. The simulations reveal non-uniform protonation behaviour within the fibril core, with specific glutamate residues titrating at substantially lower pH than terminal sites. These protonation changes correlate with pH-dependent changes in fibril flexibility, indicating transitions between distinct electrostatic stabilization regimes. The results demonstrate how coupling between structure and protonaion governs fibril stability and highlighting why such behaviour cannot be captured using fixed-protonation molecular dynamics.

Stefan Hervø-Hansen

Specially Appointed Researcher

My research interests include molecular simulation methods, free energy calculations, and rational macromolecular design.