Helix-coil transition and conformational deformity in Aβ₄₂-monomer: a case study using the Zn²⁺ cation

Abstract

The metal ions (like Fe${}^{2+},$ Zn²⁺, Cu${}^{2+}$) are known to influence the amyloid beta (Aβ) aggregation. In this study, we have examined the conformational and dynamical changes during the coordination of Aβ-monomer with the Zn${}^{2+}$ ion using all-atom molecular dynamics (MD) simulations using explicit solvent models. We have probed the unfolding of the full-length Aβ₄₂ monomer both inclusive and exclusive of the Zn${}^{2+}$ cation, with 1:1 ratio of the peptide and the Zn${}^{2+}$ cation. The inclusion of the Zn${}^{2+}$ cation shows differential intra-peptide interactions which has been probed using various analyses. The Helix – Coil transition of the wild type A${\beta }_{42}$ monomer is studied using the steered molecular dynamics simulations by taking the end-to-end C-α distance across the peptide. This gives an idea of the unequal intra – peptide and peptide – water interactions being found across the length of the Aβ monomer. The transition of an α-helix dominated wild-type (WT) Aβ structure to the unfolded coil structure gives significant evidence of the intra-peptide hydrogen bonding shifts in the presence of the Zn${}^{2+}$ cation. This accounts for the structural and the dynamical variations that take place in the Aβ monomer in the presence of the Zn${}^{2+}$ cation to mimic the conditions/environment at the onset of fibrillation.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamics
• amyloid β peptide
• steered molecular dynamics
• helix to coil transition

Acknowledgments

The authors gratefully acknowledge NISER Bhubaneswar for the computational resources. The authors thank Mr. Mitradip Das (TIFR, Mumbai) for helping with the mdp files of the gmx pull simulations.

Supporting information

The supporting information consists of the initial snapshots (S1), final snapshots of the protein structures (S2), hydrogen bonding profiles (S3–S5), contact maps (S6–S7) and the DSSP timelines for the multiple simulations (S8–S9), the mdp file of the pull simulations along with the histograms of the PMF calculations (S10–S12).

Disclosure statement

No potential conflict of interest was reported by the authors.