Constant pH Molecular Dynamics Simulation of pH Effects on Amyloid-β Structure, Dynamics, and Metal-Binding

Abstract

We report the first molecular dynamics simulations to examine the effect of pH on the structure, dynamics, and metal-binding ability of amyloid-β, the peptide implicated in the onset of Alzheimer's disease. We show that in the pH range of 6 to 8 only histidine residues show variable protonation, that predicted pKa values are in agreement with experimental data, and that changes in pH affect the size, flexibility, and secondary structure of the peptide. The binding of Cu(II) or Zn(II) to the peptide induces a shift of 1 to 1.5 pKa units in unbound histidine residues, while metal binding modes associated with higher pH induce significant changes in peptide structure. We speculate on the significance of these findings on results showing pH dependence as well as on Cu(II) and Zn(II) modulation of aggregation of Amyloid-β.

Keywords: amyloid‐β; constant pH; copper; molecular dynamics; secondary structure; zinc.

Scheme 1

Variation in metal binding modes with pH. The apical position on the Cu(II) complexes is not shown for simplicity. Component I is the major species at lower pH values and component II at higher pH values. For simplicity, we do not distinguish between His binding via the N_δ or N_ε nitrogen atoms.

Figure 1

Most populated clusters of Cu‐ and Zn‐complexes of Aβ1‐16 at pH closest to pKa (6.0 for Cu, 5.5 for Zn). The metal ion is shown as a teal sphere, coordinating residues and His13 as lines, with hydrogens omitted for clarity. Histidine residues are shown as “Hip” since the constant pH MD method used requires this designation.

Figure 2

Histogram of radius of gyration (Rg) values of apo‐Aβ1‐40 at different pH values, obtained from 600 ns constant pH simulation.

Figure 3

Percentage occurrence of salt‐bridge interactions at pH 6 between His and COO⁻ containing residues in apo‐Aβ1‐40 at pH 6, obtained from 600 ns constant pH simulation.

Figure 4

Inter‐residue contact maps of apo‐Aβ1‐40 at different pH values, obtained from 600 ns constant pH simulation (scale in Å).

Figure 5

Secondary structure propensity of apo‐Aβ1‐40 at different pH values, expressed as a fraction of frames from 600 ns MD simulation.

Figure 6

A most populated cluster of Aβ40 at different pH; red: helix, blue: turn, white: coil. Histidine residues are shown as ball‐and‐stick, without hydrogens for clarity: all His are contained in the N‐terminal region.

Figure 7

Histogram of radius of gyration (Rg) values of components I and II Cu and Zn complexes with Aβ1‐40, obtained from 600 ns constant pH simulation.

Figure 8

Most populated cluster of each type of metal‐Aβ1‐40 complex. Metal coordinating residues are shown, without hydrogens for clarity: all are contained in the N‐terminal region.

Figure 9

Secondary structure propensity of Cu and Zn complexes with Aβ40 expressed as a fraction of frames from 600 ns MD simulation.