Insights into proton transfer dynamics in histidine tautomers of amyloid-β (1-40)

Histidine tautomerization within amyloid beta (Aβ) peptides is crucial in understanding the molecular mechanisms underlying Alzheimer's disease and its potential therapeutic strategies. Despite its significance, the proton transfer dynamics between histidine residues in Aβ-40 at the protein level remain insufficiently explored due to the complexity of solvent effects and the computational challenges of large-scale simulations. This study conducted fully quantum mechanical molecular dynamics (QM-MD) simulations coupled with metadynamics (MTD) to investigate the tautomerization process between histidine tautomers in Aβ-40 within an aqueous environment. Using the divide-and-conquer density-functional tight-binding (DC-DFTB) method, a system of ~3000 atoms was modeled to capture the atomic-scale interactions. MTD simulations revealed that water molecules mediate the tautomerization of histidine residues, HIS 13 and HIS 14, stabilizing specific tautomeric forms. The two-dimensional well-tempered MTD (2D WTMTD) results identified a reaction barrier of approximately 3.51 kcal mol^-1 for tautomerization. This study represents the first comprehensive QM-MD/MTD investigation of histidine tautomerization in amyloid beta peptides, offering insights into the tautomerization process.