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

Context Existing researches confirmed that beta amyloid (A beta) has a high affinity for the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), associating closely to Alzheimer's disease. The majority of related studies focused on the experimental reports on the neuroprotective role of A beta fragment (A beta(x)), however, with a lack of investigation into the most suitable binding region and mechanism of action between A beta fragment and alpha 7nAChR. In the study, we employed four A beta(1-42) fragments A beta(x), A beta(1-16), A beta(10-16), A beta(12-28), and A beta(30-42), of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with alpha 7nAChR. Methods The protein-ligand docking server of CABS-DOCK was employed to obtain the alpha 7nAChR-A beta(x) complexes. Only the top alpha 7nAChR-A beta(x) complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which alpha 7nAChR-A beta(x) interactions' dynamic behavior and specific locations of these different A beta(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 A beta(x). Two distinct results for the first three and fourth A beta(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.