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ATP Converts Aβ42 Oligomer into Off-Pathway Species by Making Contact with Its Backbone Atoms Using Hydrophobic

Ikuo Kurisaki1, Shigenori Tanaka1

  • 1Department of Computational Science, Graduate School of System Informatics , Kobe University , 1-1 Rokkodai-cho, Nada-ku , Kobe 657-8501 , Japan.

The Journal of Physical Chemistry. B
|October 24, 2019
PubMed

Insights

Adenosine triphosphate (ATP) does not directly dissolve amyloid-beta 42 (Aβ42) oligomers. Instead, ATP binding to Aβ42 prevents further aggregation, guiding it away from fibril formation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Amyloid β 1-42 (Aβ42) aggregation is central to Alzheimer's disease pathology.
  • The precise role of Adenosine triphosphate (ATP) in Aβ42 clearance and its mechanism remain unclear.
  • Understanding Aβ42-ATP interactions is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the microscopic mechanism by which ATP influences the conformational changes and stability of Aβ42 oligomers.
  • To elucidate the role of ATP in the dissociation and aggregation processes of Aβ42.

Main Methods:

  • All-atom molecular dynamics simulations were employed to study Aβ42 pentamer and tetramer (Aβ42(9)) interactions with ATP.
  • Analysis focused on conformational changes, thermodynamic stability, and dissociation dynamics of Aβ42 protomer dimers.

Main Results:

  • ATP binding induced conformational changes in Aβ42(9), including interprotomer twisting and intraprotomer peeling, accelerating dimer dissociation.
  • ATP itself did not directly promote the dissociation of Aβ42 dimers or monomers.
  • ATP binding prevented Aβ42 monomer re-aggregation and steered oligomers towards non-fibrillar pathways.

Conclusions:

  • ATP's role in Aβ42 clearance is indirect, primarily by inhibiting further aggregation rather than direct dissolution.
  • The hydrophobic adenosine moiety of ATP interacts with Aβ42 backbone atoms, influencing its conformational state.
  • These findings offer insights into ATP's function in modulating Aβ42 fibril formation, irrespective of fibril structure.

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