Structure Comparison of Beta Amyloid Peptide Aß 1-42 Isoforms. Molecular Dynamics Modeling.
J Chem Inf Model
; 64(3): 918-932, 2024 02 12.
Article
in En
| MEDLINE
| ID: mdl-38241093
ABSTRACT
Beta amyloid peptide Aß 1-42 (Aß42) 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 Aß42 isoforms that we discuss here that are highly neurotoxic and lead to the early onset of AD. Aß42 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 Aß42 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 Aß42 and Aß16 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 Aß42 and Aß16 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 Aß42 wild type, isoD7, pS8, D7H, and H6R-Aß42 and Aß16 wild type, isoD7, pS8, D7H, and H6R-Aß16. 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 Aß42 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Peptides
/
Alzheimer Disease
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Chem Inf Model
Journal subject:
INFORMATICA MEDICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
RUSSIA
Country of publication:
United States