Exploring ensemble structures of Alzheimer’s amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift

Abstract

Aggregation of intrinsically disordered amyloid β (Aβ) is a hallmark of Alzheimer's disease. Although complex aggregation mechanisms have been increasingly revealed, structural ensembles of Aβ monomers with heterogeneous and transient properties still hamper detailed experimental accesses to early events of amyloidogenesis. We herein developed a new mathematical tool based on multiple linear regression to obtain the reasonable ensemble structures of Aβ monomer by using the solution nuclear magnetic resonance (NMR) and molecular dynamics simulation data. Our approach provided the best-fit ensemble to two-dimensional NMR chemical shifts, also consistent with circular dichroism and dynamic light scattering analyses. The major monomeric structures of Aβ including β-sheets in both terminal and central hydrophobic core regions and the minor partially-helical structures suggested initial structure-based explanation on possible mechanisms of early molecular association and nucleation for amyloid generation. A wide-spectrum application of the current approach was also indicated by showing a successful utilization for ensemble structures of folded proteins. We propose that multiple linear regression in combination to experimental results will be highly promising for studies on protein misfolding diseases and functions by providing a convincing template structure.

An amphiphilic material arginine–arginine–bile acid promotes α-synuclein amyloid formation

“…As observed previously, 50,51 Aβ42 showed a pattern of largely disordered proteins and peptides (Fig. 3C).…”

Unveiling the impact of oxidation-driven endogenous protein interactions on the dynamics of amyloid-β aggregation and toxicity

“…It should be noted that we chose the initial structure of Aβ 42 for MD simulations from conformational ensembles identified based on a combination of experimental and theoretical data. 29 The monomeric Aβ 42 structure, which occupied the largest population in the conformational ensembles, was selected as a template. Although the initial structure of Aβ 42 can influence the trajectories and results of MD simulations, our computational results may provide valuable insights into the molecular interaction between Cyt c and Aβ 42 .…”

“…Molecular dynamics (MD) simulations guided by experimental data can present a detailed picture for protein-protein interactions. [25][26][27] To investigate the potential binding modes of Cyt c to Ab 42 , MD simulations were carried out with an X-ray crystal structure of Cyt c (PDB 1HRC) 28 and an Ab 42 conformer acquired from the MD simulation data, 29 as shown in Fig. 2A.…”

“…The model on the le involves Glu11, Lys16, and Val18 close to the self-recognition site in Ab 42 as the major binding region with Cyt c. The carboxylate group of Glu11 forms a hydrogen bond with a length of 1.9 Å against the side chain of Lys87 in Cyt c. Furthermore, the side chain of Lys16 in Ab 42 interacts with Glu66 in Cyt c in an average length of 1.9 Å and its backbone carbonyl group exhibits an additional hydrogen bond with Lys88 in Cyt c. The hydrophobic Val18 residue of Ab 42 resides between two positioned alkyl chains of the aforementioned Lys87 and Lys88 in Cyt c. In the other probable model, Thr28 in Cyt c plays a key role in interacting with the C-terminal region of Ab 42 that is anchored to Cyt c by the following two hydrogen bonds: (i) the backbone carbonyl group of Val39 in Ab 42 and the backbone amide moiety of the Thr28 in Cyt c; (ii) the backbone carbonyl group of Ile41 in Ab 42 and the side chain hydroxyl group of Thr28 in Cyt c. It should be noted that we chose the initial structure of Ab 42 for MD simulations from conformational ensembles identied based on a combination of experimental and theoretical data. 29 The monomeric Ab 42 structure, which occupied the largest population in the conformational ensembles, was selected as a template. Although the initial structure of Ab 42 can inuence the trajectories and results of MD simulations, our computational results may provide valuable insights into the molecular interaction between Cyt c and Ab 42 .…”

Cytochrome c as a distinct modulator of amyloid-beta amyloidogenesis in a peroxide-dependent manner

“…To investigate the potential binding modes of Cyt c to Ab42, MD simulations were carried out with an X-ray crystal structure of Cyt c (PDB 1HRC 22 ) and an Ab42 conformer acquired from the MD simulation data 23 , as shown in Fig. 1a.…”