Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

Abstract

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1–40 and Aβ1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1–40 peptides can only assume U-shaped conformations while Aβ1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

“…Among different lengths of Aβ peptides, senile aggregates are mostly made by the Aβ 40 fibrils, but the most toxic species are the Aβ 42 ones, due to their intrinsic tendency to self-assembly [5]. The stability of these structures is strongly linked with the progression and severity of the disease, and in the last years, many efforts have been made to characterize the molecular stability of amyloid aggregates [6][7][8][9][10][11][12][13][14].…”

Ameliorating amyloid aggregation through osmolytes as a probable therapeutic molecule against Alzheimer's disease and type 2 diabetes

“…95 Atomistic simulations showed oligomerization as a result of anti-parallel b-sheet formation between C-terminal segments. The central [20][21][22][23][24][25][26][27][28][29] and Cterminal [30][31][32][33][34][35][36][37] segments aid in maintaining stable secondary structures and encouraging intermolecular interactions. The hydrophobic amino acids (I26 and L27) facilitate oligomeric conformations and help in the elongation of brils.…”

“…28 Grasso et al investigated the conformational dynamics and stabilities of S-shaped and U-shaped Ab assemblies because the C-terminal residues are involved in many interactions. 29 They also claimed that the U-shaped motif is signicantly described by distortions leading to an assembly with higher disorder. 29 Alexandre et al analysed the importance of the conserved disulde bond in hIAPP between two cysteine at positions 2 and 7 using a combination of experimental studies and MD simulations.…”

“…29 They also claimed that the U-shaped motif is signicantly described by distortions leading to an assembly with higher disorder. 29 Alexandre et al analysed the importance of the conserved disulde bond in hIAPP between two cysteine at positions 2 and 7 using a combination of experimental studies and MD simulations. 30 A wild type fragment (hIAPP 1-8 ) led to amyloid aggregation through a different pathway than a fragment without disulde bonds and a fragment having cysteine mutated to serine at positions 2 and 7; hence, they claimed that an intact disulde bond might help protect from amyloid aggregation because of decreased interpeptide hydrogen bonding 30 .…”

Recent Advances by In Silico and In Vitro Studies of Amyloid-β 1-42 Fibril Depicted a S-Shape Conformation

“…However, the S-shape structure is more complete because it possesses more amino acid residues in the N-terminal (PDB: 5KK3, 2MXU, and 2NAO; Figure 3) [98,99]. Therefore, several differences have been found in relation to the inter-sheet side chain contacts, hydrophobic contacts among the strands, and salt bridges in stabilizing the U- and S-shape protein aggregates [100].…”