Molecular Dynamics Simulations of Monomeric and Tetrameric Amyloid β_1‐42 Peptides with <scp>d</scp>‐Aspartic Acid Residues

Amyloid β_1-42 (Aβ_1-42) peptide includes three aspartic acid (Asp) residues. It is known that these Asp residues undergo stereoinversion to d-Asp in ageing tissues, a process that promotes β-sheet structure formation. In this study, the 3D structures of Aβ_1-42 monomers and tetramers containing d-Asp residues are analyzed using molecular dynamics (MD) simulations. Seven types of mutants are generated by stereoinverting the three Asp residues, and monomer MD simulations are performed using an implicit solvent model for all seven mutants and the wild type. Following these implicit solvent simulations, tetramer MD simulations using explicit water molecules are conducted for the wild type and three mutants previously reported to form secondary structures in experimental studies. The MD simulations of Aβ_1-42 monomers with implicit solvent successfully reproduced the trend of increased β-structure formation caused by D-Asp7 and d-Asp23. However, the effects of d-Asp1 are only captured in tetramer simulations using explicit water. These findings suggest that explicit water is necessary to accurately model peptide-peptide interactions and that multimer simulations are essential for investigating structural features, such as β-sheet formations and aggregation in proteins containing d-amino acids.