Protein aggregates such as oligomers and amyloid fibrils cause more than 40 diseases. For example, Alzheimer’s disease is caused by aggregated amyloid-β (Aβ) peptides. Aβ peptide usually consists of 40 or 42 amino acid residues. Aβ peptide with 40 residues is referred to as Aβ40, and that with 42 residues is referred to as A42. We have performed molecular dynamics (MD) simulations to understand the aggregation and disaggregation mechanisms of Aβ peptides. To analyze the aggregation process, we performed Hamiltonian replica-permutation MD simulations for Aβ40 and Aβ42 [1]. We found that the key residue for the Aβ42 dimerization is Arg5 in the oligomerization process. This residue stabilizes the β-hairpin structure and promotes the intermolecular β-sheet. We also revealed why Aβ42 aggregates faster than Aβ40. We have also performed MD simulations of RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This protein is a drug target for coronavirus disease 2019 (COVID-19) because it plays the most important role in the replication of the RNA genome. Nucleotide analogs such as remdesivir and favipiravir interfere with the RNA replication by RdRp. We performed all-atom molecular dynamics simulations to clarify the recognition mechanism of RdRp for these drugs [2]. The ligand recognition ability of RdRp decreased in the order of remdesivir, favipiravir, and ATP. We also identified recognition paths. It was observed that the multiple lysine residues of RdRp carried the ligands to the binding site like a “bucket brigade”. We also observed another path,
in which the ligands directly reached the binding site. Our findings contribute to the understanding of the efficient ligand recognition by RdRp at the atomic level.

[1] S. G. Itoh, M. Yagi-Utsumi, K. Kato, and H. Okumura, ACS Chem. Neurosci. 13 (2022) 3139.
[2] S. Tanimoto, S. G. Itoh, and H. Okumura, Biophys. J. 120 (2021) 3615.