A comprehensive understanding of the aggregation mechanism in amyloid beta 42 (Ab42) peptide is imperative to develop therapeutic drugs to prevent or treat Alzheimer’s disease. Because of its high flexibility and lack of native tertiary structures of Ab42, 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 Ab42 by using a newly developed but not extensively applied Amber force field (ff14IDPSFF) for intrinsically disordered proteins. 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 from MD simulation are force field and initial structure dependent. The force field ff14IDPSFF sampled a high ratio of disordered structures and diverse β-strand secondary structures; in contrast, ff14SB overestimated the helicity of the Ab42α-helix. The conformation obtained from the Aβ42β-strand structure maintained balanced content in the disordered and helical structures when simulated by ff14SB, but the conformers clearly favored disordered and β-sheet structures in ff14IDPSFF. The results obtained from ff14IDPSFF reproduced the NMR chemical shifts, secondary structure content and radius of gyration qualitatively well. In-depth peptide and cluster analysis revealed some characteristic features that may link to early onset of the fibril-like structure; C-terminal region (mainly M35-V40) featured in-registered anti-parallel β-strand (β-hairpin) conformations with both force fields in two different structures. In addition, ff14IDPSFF could recover some unfolded and disordered structures that were easily accessible to water in the peptide, which is shown with higher solvent accessible surface area. Our work should expand the knowledge in understanding the force field and structure dependency in MD simulations and reveals the underlying structural mechanism–function relationship in Ab42 peptides.

Modeling structural interconversion in Alzheimers’ amyloid beta peptide with classical and intrinsically disordered protein force fields

ACS Fall 2021

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