Theoretical Insights into Mutation and Histidine Tautomerism Effects on Tau Proteins.

Research on misfolding of tau proteins will help to better understand the formation process of neurofibrillary tangles, a hallmark of Alzheimer's disease. Mutation and histidine tautomeric effects have been considered the two most important inherent factors for tau protein misfolding. In current research, replica-exchange molecular dynamics (REMD) were performed to characterize the structural properties of the key fragment R3 of tau protein under the collective effects of P332L mutation and histidine tautomerism. Simulation results suggest that though the content β-sheet of P332L R3 εδ isomer is slightly lower than that of the WT P332L R3 fragment, the total stable secondary structures including β-sheet and helix of P332L R3 isomers are generally more prevalent than those of wild type R3, which may be the reason that P332L R3 has a higher aggregation tendency. Further analysis showed that the hydrogen bond networks are affected by the mutation and histidine tautomerism. Furthermore, the interactions between N-terminus and C-terminus play a crucial role in β-hairpin formation in all isomers. The current study will contribute to revealing the collective effects of P332L and histidine tautomerism on the misfolding of tau proteins.