Helix-to-sheet transition of the Aβ42 peptide revealed using an enhanced sampling strategy and Markov state model.

The self-assembly of Aβ peptides into toxic oligomers and fibrils is the primary cause of Alzheimer's disease. Moreover, the conformational transition from helix to sheet is considered a crucial step in the aggregation of Aβ peptides. However, the structural details of this process still remain unclear due to the heterogeneity and transient nature of the Aβ peptides. In this study, we developed an enhanced sampling strategy that combines artificial neural networks (ANN) with metadynamics to explore the conformational space of the Aβ42 peptides. The strategy consists of two parts: applying ANN to optimize CVs and conducting metadynamics based on the resulting CVs to sample conformations. The results showed that this strategy achieved better sampling performance in terms of the distribution of sampled conformations. The sampling efficiency is increased by 10-fold compared to our previous Hamiltonian Exchange Molecular Dynamics (MD) and by 1000-fold compared to ordinary MD. Based on the sampled conformations, we constructed a Markov state model to understand the detailed transition process. The intermediate states in this process are identified, and the connecting paths are analyzed. The conformational transitions in D23-K28 and M35-V40 are proven to be crucial for aggregation. These results are helpful in clarifying the mechanism and process of Aβ42 peptide aggregation. D23-K28 and M35-V40 can be identified as potential targets for screening and designing inhibitors of Aβ peptide aggregation.