Exploring the Early Stages of the Amyloid Aβ(1–42) Peptide Aggregation Process: An NMR Study

Abstract

Alzheimer’s disease (AD) is a neurodegenerative pathology characterized by the presence of neurofibrillary tangles and amyloid plaques, the latter mainly composed of Aβ(1–40) and Aβ(1–42) peptides. The control of the Aβ aggregation process as a therapeutic strategy for AD has prompted the interest to investigate the conformation of the Aβ peptides, taking advantage of computational and experimental techniques. Mixtures composed of systematically different proportions of HFIP and water have been used to monitor, by NMR, the conformational transition of the Aβ(1–42) from soluble α-helical structure to β-sheet aggregates. In the previous studies, 50/50 HFIP/water proportion emerged as the solution condition where the first evident Aβ(1–42) conformational changes occur. In the hypothesis that this solvent reproduces the best condition to catch transitional helical-β-sheet Aβ(1–42) conformations, in this study, we report an extensive NMR conformational analysis of Aβ(1–42) in 50/50 HFIP/water v/v. Aβ(1–42) structure was solved by us, giving evidence that the evolution of Aβ(1–42) peptide from helical to the β-sheet may follow unexpected routes. Molecular dynamics simulations confirm that the structural model we calculated represents a starting condition for amyloid fibrils formation.

Structural analysis of a simplified model reproducing SARS-CoV-2 S RBD/ACE2 binding site

“…The secondary structure of the ACE 21–42 peptide was studied by CD and NMR techniques in a solution mixture of HFIP/water 50/50 v/v [ 32 ]. Taking advantage of the physical-chemical properties of the fluorinated solvents, HFIP/water mixtures have been extensively used to study the conformation of partially hydrophobic peptides [ 29 , 33 , 34 , 35 , 36 ].…”

Inhibition Effect and Molecular Mechanisms of Quercetin on the Aβ42 Dimer: A Molecular Dynamics Simulation Study

“…The three-dimensional (3D) structure of the monomeric Aβ42 peptide is obtained from the Protein Data Bank, and the amino acid residue sequence of the Aβ42 monomer is D 1 AE­FRHD­SGY 10 E­VHH­QKL­VFF 20 A­EDVG­SNK­GA 30 II­GLM­VGG­VV 40 I­A 42 . Compared to the NMR structure of the Aβ42 peptide (PDB ID: 1IYT) taken from the solvent system of the 80/20 hexafluoroisopropanol (HFIP)/water proportion which is a prevalent α-helix structure as well as the NMR structure of the Aβ42 peptide (PDB ID: 1Z0Q) derived from the solvent system of 30/70 HFIP/water proportion which is the prevalent bend structure, the 3D NMR conformation of the Aβ42 peptide (PDB ID: 6SZF) which is from the solvent system of 50/50 HFIP/water proportion is intermediate in regularity and rich in coil . Therefore, model 1 of the NMR structure in PDB file 6SZF is utilized as a topology model of MD simulations (Figure a).…”

AmyP53 Prevents the Formation of Neurotoxic β-Amyloid Oligomers through an Unprecedent Mechanism of Interaction with Gangliosides: Insights for Alzheimer’s Disease Therapy

“…The paradigm that has dominated clinical research on Alzheimer’s disease for more than 30 years points to amyloid plaques as the root cause of the disease [ 4 ]. These plaques are essentially made up of the Alzheimer’s β-amyloid peptide (Aβ 1–42 ), a small protein which self-aggregates in an aqueous medium to form larger assemblies by fibrillation [ 5 , 6 , 7 ]. Logically, most therapeutic strategies converged to target and destroy amyloid plaques, with the hope to cure the disease.…”