posted on 2024-01-19, 17:39authored byAnna P. Tolstova, Alexander A. Makarov, Alexei A. Adzhubei
Beta
amyloid peptide Aβ 1–42 (Aβ42) has a unique
dual role in the human organism, as both the peptide with an important
physiological function and one of the most toxic biological compounds
provoking Alzheimer’s disease (AD). There are several known
Aβ42 isoforms that we discuss here that are highly neurotoxic
and lead to the early onset of AD. Aβ42 is an intrinsically
disordered protein with no experimentally solved structure under physiological
conditions. The objective of this research was to establish the appropriate
molecular dynamics (MD) methodology and model a uniform set of structures
for the Aβ42 isoforms that form the core of this study. For
that purpose, force field selection and verification including convergence
testing for MD simulations was made. Replica exchange MD and conventional
MD modeling of several Aβ42 and Aβ16 isoforms that have
neurotoxic and amyloidogenic effects impacting the severity of Alzheimer’s
disease were carried out with the optimal force field and solvent
parameters. A standardized ensemble of structures for the Aβ42
and Aβ16 isoforms covering 30–50% of the conformational
ensembles extracted from the free energy minima was calculated from
MD trajectories. The resulting data set of modeled structures includes
Aβ42 wild type, isoD7, pS8, D7H, and H6R-Aβ42 and Aβ16
wild type, isoD7, pS8, D7H, and H6R-Aβ16. The representative
structures are given in the Supporting Information; they are open
for public access. In the study, we also evaluated the differences
between the structures of Aβ42 isoforms and speculate on their
possible relevance to the known functions. Utilizing several representative
structures for a single disordered protein for docking, with their
subsequent averaging by conformations, would markedly increase the
reliability of docking results.