Conformational features of the Aβ₄₂ peptide monomer and its interaction with the surrounding solvent

Abstract

Accumulation of the amyloid beta (Aβ) peptide in the brain is responsible for debilitating neurodegenerative diseases, such as Alzheimer's disease (AD). We have carried out atomistic molecular dynamics simulations of the full-length Aβ peptide monomer with a wide range of conformations at room temperature. Efforts have been made to probe the conformational features of different segments of the peptide, namely the two terminal segments (N-term and C-term), the central hydrophobic regions (hp1 and hp2) and the central turn region joining hp1 and hp2, and their nonuniform influence on the spatial arrangements and binding energies of the surrounding water molecules. Our calculations reveal fluctuating conformations of the monomers with the formation and breaking of different secondary structural elements. In particular, it is noticed that the Aβ monomers exhibit a propensity to either retain or transform into a helical form toward the N-term region and a β-strand-like form near the C-term segment. Besides, heterogeneous conformational flexibility of the Aβ monomers has been found to be correlated with the corresponding nonuniform entropy gains. Additionally, our calculation further reveals a heterogeneous hydration environment around the peptide. It is found that irrespective of the Aβ peptide conformations and their nonuniform fluctuations, water molecules around the hydrophobic hp1 and hp2 segments are relatively weakly bound. This is an important observation, as in the presence of other monomers such weakly bound water molecules around hp1 and hp2 are expected to be easily displaced during the hydrophobic collapse that leads to Aβ aggregation.

Computational Approaches to Understanding the Biological Behaviour of Intrinsically Disordered Proteins

“…In this study, AMD, in agreement with experimental data, revealed strong structural propensity of four homologous sequences in repeat domains to form turns and highlighted the potential of this specific conformational transition as an inhibitory mechanism against pathological transformation. Our previous studies have implemented AMD to sample the conformational space of full-length A peptide, which has been further used to understand the correlations with the structure and dynamics of surrounding water molecules [69][70] . The probability of finding a molecular system in one state or another depends on the free-energy difference between two states.…”

The impact of water on the ambivalent behavior and paradoxical phenomenon of the amyloid-β fibril protein

“…The amino acid residues of the Aβ 42 fibril peptide chain is given below (Scheme 1) (18), where the colors correlate to the hydropathy index (24): green = polar [(−3.2) − (−4.5)] and red = non-polar [(+4.5) - (+2.8)]. As can be seen, the Aβ 42 molecule's sequence includes a polar/non-polar proportion of 14/14, where the N-terminal half has 10 polar and the C-terminal has eight non-polar residues, i.e.…”

“…Also the thermodynamic parameters of the Aβ 42 monomer fibril were calculated (18). Considering the calculated binding energies [(tagged potential energy (TPE) (U TPE )] of the hydration water according to the segments are as follows: As a reference, the average TPE of the pure bulk water is −19.7 kcal mol The extracellular Aβ 40 and Aβ 42 fibril peptides Petkova and coworkers (28) studied in detail the molecular structure of the Aβ 40 fibril protein using the solid NMR technique, and also using X-ray fiber diffraction, transmission electron microscopy and MD simulations.…”

“…Aβ peptides are cleaved from a transmembrane protein called the amyloid precursor protein (APP) by proteolytic cleavages of the β-and γ-secretases (18). There are two types of these fibril protein molecules: namely the Aβ 40 and Aβ 42 monomers.…”

“…The third team also studied this molecule by cryo-electron microscopy (22). On the other hand, a hairpin-like structure of the full-length Aβ 42 monomer was determined by NMR (18) and by small angle neutron scattering (23) in the presence of organic co-solvents (e.g. hexafluoroisopropanol), as shown in Figure 1.…”