Structures of the Alzheimer’s Wild-Type Aβ1-40 Dimer from Atomistic Simulations

Abstract

We have studied the dimer of amyloid beta peptide Aβ of 40 residues by means of all-atom replica exchange molecular dynamics. The Aβ-dimers have been found to be the smallest toxic species in Alzheimer's disease, but their inherent flexibilities have precluded structural characterization by experimental methods. Though the 24-μs-scale simulation reveals a mean secondary structure of 18% β-strand and 10% α helix, we find transient configurations with an unstructured N-terminus and multiple β-hairpins spanning residues 17-21 and 30-36, but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all α topologies, and one compact peptide with β-sheet structure stabilized by a rather extended peptide with α-helical content. Overall, this first all-atom study provides insights into the equilibrium structure of the Aβ1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early-stage Alzheimer's disease on a molecular level.

Polymorphism of fibrillar structures depending on the size of assembled Aβ17-42 peptides

“…Those missed transient structures may have α-helices and intramolecular β-hairpins, which were proposed in the extensive atomistic simulations for an Aβ 40 dimer47. Nevertheless, we show a variety of polymorphisms in structure depending on size.…”

Conformational Ensembles of the Wild-Type and S8C Aβ1–42 Dimers

“…35 The single-molecule states, which are the states of a single chain in the presence of another chain, 36 were determined using dihedral principal component analysis (dPCA). 37 The double-molecule states were determined using the PCA of the inverse distances between C α atoms, and the overall dimer states are the product of the single- and double-molecule states. 36 In the calculations, each system is projected on the eigenvectors obtained from the two REMD trajectories.…”

“…The collision cross-sections (CCSs) were calculated using MOBCAL 38 and the trajectory method reported in other simulations. 25,35,37 …”

Computational Approaches to Understanding the Biological Behaviour of Intrinsically Disordered Proteins

“…Rapid exchange of replicas helps overcome free energy barriers in the conformational landscape. This technique has been widely used as an explorative tool to characterize the rugged energy landscapes of IDPs [58][59][60][61][62][63][64][65][66] . Sgourakis et al 67 used REMD based methods to distinguish the conformational ensembles of two A variants (A and A ) which are key players in the pathogenesis of Alzheimer's disease (AD).…”

“…They also identified structured regions primarily in the C-terminus of A 1-42 that may be responsible for higher propensity of this peptide to form amyloid. Another study exploited REMD to provide insights into the equilibrium structure of A dimer by sampling the various transient peptide conformations and modes of organization to form the dimer 58 . Das et al 66 , using extensive atomistic REMD, studied the protective cross-interaction of experimentally revealed A2T variant of A monomer and the wild type (WT).…”