Molecular mechanism of amyloidogenicity and neurotoxicity of a pro-aggregated tau mutant in the presence of histidine tautomerism via replica-exchange simulation

Abstract

The accumulation of ΔK280 tau mutant resulting in neurotoxic oligomeric aggregates is an important but yet mysterious procedure in Alzheimer's disease (AD) development. Recently, we proposed a histidine tautomerization hypothesis of tau fibrillogenesis for the pathobiology of AD and other neuro diseases. However, the influence of neutral histidine tautomeric states on tau mutation is still unclear. Herein, we performed replica-exchange molecular dynamics (REMD) simulations to characterize structural features as well as the mode of toxic action of the ΔK280 tau mutant in the presence of histidine tautomerism. Molecular dynamics (MD) simulation results show that the δε tautomeric isomer (having a distinct global energy minimum) had the highest β-sheet structure, which adopts a sheet-rich conformer and may have significant influence on the structural behaviors of ΔK280 tau monomers. Furthermore, clustering, residual contact map, mobility and structural analysis exhibited that the presence of β-strand interactions between stable lysine 8 (K8)–asparagine 13 (N13) and valine 39 (V39)–tyrosine 43 (Y43) residues plus K31–histidine 32 (H32) and K8–N13 (strand-loop-strand [β-meander] structure) helped δε to form toxic aggregates. Moreover, H299 played a more critical role in the conformational instability of the δε than H268. Overall, the results obtained from this study may be used to arrest neurodegeneration in ΔK280 tau mutation carriers as well as increase the understanding of AD-related tau pathogenesis and strengthen the histidine tautomerism hypothesis of misfolded peptide accumulation.