Dimerization Mechanism of Alzheimer Aβ₄₀ Peptides: The High Content of Intrapeptide-Stabilized Conformations in A2V and A2T Heterozygous Dimers Retards Amyloid Fibril Formation

Abstract

Amyloid beta (Aβ) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Aβ dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Aβ dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of-register antiparallel β-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded β-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid-forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded β-sheet or inhibiting the formation of an interpeptide β-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of Aβ species.

Computational Study of the Aza‐Michael Addition of the Flavonoid (+)‐Taxifolin in the Inhibition of β‐Amyloid Fibril Aggregation

“…The structural flexibility associated to the folding of amyloid fibrils makes the selection of a reliable structural model for in silico purposes to be a challenging question. This is noted, for instance, in the complex conformational ensemble of dimeric structures of Aβ40 and Aβ42, which encompass diverse conformations differing in the secondary structure and both the tertiary and quaternary folds . Accordingly, we examined the Aβ aggregates available in the PDB in order to identify structural features that may be suitable for covalent inhibition though a conjugative mechanism, such as the presence of concave surfaces or grooves that may permit the proper accommodation of oxidized (+)‐taxifolin close to Lys16.…”

Impact of A2T and D23N Mutations on Tetrameric Aβ42 Barrel within a Dipalmitoylphosphatidylcholine Lipid Bilayer Membrane by Replica Exchange Molecular Dynamics

“…!" between two residues is smaller than 0.45 nm, the indexes , are in the range of [9,40] and the indexes , are in the range of [1,4] with ≠ . The total SC contact between two chains is the sum of all available SC between residues of two chains !"…”

Looking at the Disordered Proteins through the Computational Microscope

“… 54 , 58 The effect of homotypic and heterotypic interactions between WT, A2V, and A2T monomers on the Aβ 40/42 dimeric landscape has been also studied using atomistic simulations. 64 − 68 While aggregation-prone WT/WT and A2V/A2V homodimers are found to populate highly stabilized interpeptide structures with a high content of interpeptide β-sheets or β-hairpin conformations, the AD-protective WT/A2V and WT/A2T Aβ 42 heterotypical interactions favored formation of weak dimers that are highly disordered and collapsed in nature. 67 − 69 These results suggest that A2V and A2T mutations differentially alter the misfolding into the transient monomeric β-hairpin structures that are thought to play a crucial role in aggregation, as suggested by earlier simulations 70 , 71 and experiments.…”