Modeling structural interconversion in Alzheimers' amyloid beta peptide with classical and intrinsically disordered...

A comprehensive understanding of the aggregation mechanism in amyloid beta 42 (Aβ42) peptide is imperative for developing therapeutic drugs to prevent or treat Alzheimer's disease. Because of the high flexibility and lack of native tertiary structures of Aβ42, molecular dynamics (MD) simulations may help elucidate the peptide's dynamics with atomic details and collectively improve ensembles not seen in experiments. We applied microsecond-timescale MD simulations to investigate the dynamics and conformational changes of Aβ42 by using a newly developed Amber force field (ff14IDPSFF). We compared the ff14IDPSFF and the regular ff14SB force field by examining the conformational changes of two distinct Aβ42 monomers in explicit solvent. Conformational ensembles obtained by simulations depend on the force field and initial structure, Aβ42^α-helix or Aβ42^β-strand. The ff14IDPSFF sampled a high ratio of disordered structures and diverse β-strand secondary structures; in contrast, ff14SB favored helicity during the Aβ42^α-helix simulations. The conformations obtained from Aβ42^β-strand simulations maintained a balanced content in the disordered and helical structures when simulated by ff14SB, but the conformers clearly favored disordered and β-sheet structures simulated by ff14IDPSFF. The results obtained with ff14IDPSFF qualitatively reproduced the NMR chemical shifts well. In-depth peptide and cluster analysis revealed some characteristic features that may be linked to early onset of the fibril-like structure. The C-terminal region (mainly M35-V40) featured in-registered anti-parallel β-strand (β-hairpin) conformations with tested systems. Our work should expand the knowledge of force field and structure dependency in MD simulations and reveals the underlying structural mechanism-function relationship in Aβ42 peptides. Communicated by Ramaswamy H. Sarma.