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

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Understanding amyloid beta 42 (Aβ42) aggregation is crucial for Alzheimer's disease therapeutics.
• Aβ42's flexibility and lack of defined structures challenge experimental analysis.
• Molecular dynamics (MD) simulations offer atomic-level insights into peptide dynamics.

Purpose of the Study:

• To investigate Aβ42 dynamics and conformational changes using microsecond-timescale MD simulations.
• To compare the performance of a new Amber force field (ff14IDPSFF) against a standard one (ff14SB).
• To explore the relationship between force fields, initial structures, and sampled conformations.

Main Methods:

• Microsecond-timescale molecular dynamics (MD) simulations of Aβ42 monomers.
• Utilized the novel Amber ff14IDPSFF and standard ff14SB force fields.
• Simulations were initiated from both α-helix and β-strand conformations in explicit solvent.

Main Results:

• The ff14IDPSFF force field sampled more disordered and diverse β-strand structures compared to ff14SB.
• ff14SB favored helicity from α-helix starting points, while ff14IDPSFF favored disordered/β-sheet structures from β-strand starting points.
• ff14IDPSFF results showed good agreement with experimental NMR chemical shifts and revealed potential fibril-like structural features, including β-hairpins in the C-terminal region.

Conclusions:

• Force field choice and initial structure significantly impact MD simulation outcomes for Aβ42.
• The ff14IDPSFF force field provides a more accurate representation of Aβ42's conformational flexibility.
• Findings enhance understanding of Aβ42 structural dynamics and their link to Alzheimer's disease pathogenesis.