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

Journal of Biomolecular Structure & Dynamics
Kingsley Y WuChia-En A Chang

Abstract

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, Aβ42α-helix or Aβ42β-strand. The ff14IDPSFF sampled a high ratio of disordered structures and diverse β-strand secondary structures; in contrast, ff14SB favored helicity during the Aβ42α-helix simulations. The conformations obtained from Aβ42β-strand simulations maintained a balanced content in the disordered and helical structures when simulated by ff14SB, but the conformers clearly favored disordered a...Continue Reading

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