Structures of the Amyloid β-Peptides Aβ_1–40 and Aβ_1–42 as Influenced by pH and a d-Peptide

Abstract

In this simulation study, we present a comparison of the secondary structure of the two major alloforms of the Alzheimer's peptide (Aβ(1-40) and Aβ(1-42)) on the basis of molecular dynamics (MD) simulations on thea microsecond time scale using the two GROMOS96 force fields ffG43a2 and ffG53a6. We observe peptide and force-field related differences in the sampled conformations of Aβ(1-40) and Aβ(1-42), which we characterize in terms of NMR chemical shifts calculated from the MD trajectories and validate against the corresponding experimental NMR results. From this analysis, we can conclude that ffG53a6 is better able to model the structural propensities of Aβ(1-40) and Aβ(1-42) than ffG43a2. Furthermore, we provide a description of the influences of pH and binding of D3, a 12-residue D-enantiomeric peptide with demonstrated antiamyloid effects, on the structure of Aβ(1-42). We demonstrate that, under slightly acidic conditions, protonation of the three histidine residues in Aβ(1-42) promotes the formation of β-sheets via a reduction in electrostatic repulsion between the two terminal regions. Our studies further reveal that the binding between D3 and Aβ(1-42) is driven by electrostatic interactions between negatively charged Aβ(1-42) residues and the five positively charged arginine residues of D3. The binding of D3 was found to induce large conformational changes in the amyloid peptide, with a reduction in β-sheet units being the most significant effect recorded, possibly explaining the observed amyloid-inhibiting properties of the D-peptide.

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease

“…Lowering BACE-1 levels reduces neurodegeneration and behavioral defects in APP transgenic mice, pointing to its importance as therapeutic target (12). Furthermore, (iii) the protonation states of the three histidine residues in Ab (His6, His13 and His14) have been reported to promote aggregation * This work was supported, in whole or in part, by National Institutes of Health via pH-dependent effect on the formation of b-sheets and the binding of metal ions to Ab (13). Most recently, (iv) acidic luminal pH has been shown to attenuate lysosomal degradation of Ab by disrupting SORLA-Ab interaction (14).…”

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

“…Liu et al 64 employed a simulation of 50 ns in length, which is still relatively short, and the structure obtained was very similar to the starting model. To more thoroughly describe the dynamics of Aβ in aqueous solvent, considerably longer simulations are generally required for exhaustive sampling 77 and additional simulations would improve statistical reliability and allow for a more thorough evaluation of convergence within and across simulations.…”

Protein Structure Prediction: Assembly of Secondary Structure Elements by Basin‐Hopping

“…[13][14][15] In order to further improve the efficiency of the BH approach to protein structure prediction, we have implemented knowledge-based MC moves by incorporating secondary structure information from secondary structure prediction. We refer to this approach as secondary-to-tertiary basin-hopping.…”

“…The BH algorithm has been implemented in the GMIN program 69 and has already been employed to find the global minimum of peptides and peptide complexes in previous work. 5,6,[8][9][10][11][12][13][14][15]18 In GMIN, local minimization is facilitated by using a modified version of the LBFGS procedure described by Liu and Nocedal.…”