Structure Comparison of Beta Amyloid Peptide A 1-42 Isoforms. Molecular Dynamics Modeling

Beta amyloid peptide A beta 1-42 (A beta 42) 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 A beta 42 isoforms that we discuss here that are highly neurotoxic and lead to the early onset of AD. A beta 42 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 A beta 42 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 A beta 42 and A beta 16 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 A beta 42 and A beta 16 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 A beta 42 wild type, isoD7, pS8, D7H, and H6R-A beta 42 and A beta 16 wild type, isoD7, pS8, D7H, and H6R-A beta 16. 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 A beta 42 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.