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Remarked Suppression of Aβ 42 Protomer-Protomer Dissociation Reaction Elucidated by Molecular Dynamics Simulation
  • Ikuo Kurisaki,
  • Shigenori Tanaka
Ikuo Kurisaki
Kobe Daigaku - Rokkodai Chiku Campus

Corresponding Author:[email protected]

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Shigenori Tanaka
Kobe Daigaku - Rokkodai Chiku Campus
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Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-β (1-42) (Aβ 42). Seven different dimeric forms of oligomeric Aβ 42 fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ 42 protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.
14 Oct 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
18 Oct 2021Submission Checks Completed
18 Oct 2021Assigned to Editor
19 Oct 2021Reviewer(s) Assigned
24 Nov 2021Review(s) Completed, Editorial Evaluation Pending
26 Nov 2021Editorial Decision: Revise Major
25 Jan 20221st Revision Received
25 Jan 2022Submission Checks Completed
25 Jan 2022Assigned to Editor
25 Jan 2022Reviewer(s) Assigned
01 Feb 2022Review(s) Completed, Editorial Evaluation Pending
02 Feb 2022Editorial Decision: Accept
Jul 2022Published in Proteins: Structure, Function, and Bioinformatics volume 90 issue 7 on pages 1367-1375. 10.1002/prot.26319