Specific interaction from different Aβ42 peptide fragments to α7nAChR-A study of molecular dynamics simulation.

Context: Existing researches confirmed that β amyloid (Aβ) has a high affinity for the α7 nicotinic acetylcholine receptor (α7nAChR), associating closely to Alzheimer's disease. The majority of related studies focused on the experimental reports on the neuroprotective role of Aβ fragment (Aβ_x), however, with a lack of investigation into the most suitable binding region and mechanism of action between Aβ fragment and α7nAChR. In the study, we employed four Aβ_1–42 fragments Aβ_x, Aβ_1–16, Aβ_10–16, Aβ_12–28, and Aβ_30–42, of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with α7nAChR. Methods: The protein–ligand docking server of CABS-DOCK was employed to obtain the α7nAChR-Aβ_x complexes. Only the top α7nAChR-Aβ_x complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which α7nAChR-Aβ_x interactions' dynamic behavior and specific locations of these different Aβ_x fragments were identified. MM-PBSA calculations were also done to estimate the binding free energies and the different contributions from the residues in the Aβ_x. Two distinct results for the first three and fourth Aβ_x fragments in binding site, strength, key residue, and orientation, account for why the fourth fails to play a neuroprotective role at the molecular level. [ABSTRACT FROM AUTHOR]