Simulation study on the disordered state of an Alzheimer's β amyloid peptide Aβ(12–36) in water consisting of random‐structural, β‐structural, and helical clusters

The monomeric Alzheimer's β amyloid peptide, Aβ, is known to adopt a disordered state in water at room temperature, and a circular dichroism (CD) spectroscopy experiment has provided the secondary‐structure contents for the disordered state: 70% random, 25% β‐structural, and 5% helical. We performed an enhanced conformational sampling (multicanonical molecular dynamics simulation) of a 25‐residue segment (residues 12–36) of Aβ in explicit water and obtained the conformational ensemble over a wide temperature range. The secondary‐structure contents calculated from the conformational ensemble at 300°K reproduced the experimental secondary‐structure contents. The constructed free‐energy landscape at 300°K was not plain but rugged with five clearly distinguishable clusters, and each cluster had its own characteristic tertiary structure: a helix‐structural cluster, two β‐structural clusters, and two random‐structural clusters. This indicates that the contribution from the five individual clusters determines the secondary‐structure contents experimentally measured. The helical cluster had a similarity with a stable helical structure for monomeric Aβ in 2,2,2‐trifluoroethanol (TFE)/water determined by an NMR experiment: The positions of helices in the helical cluster were the same as those in the NMR structure, and the residue–residue contact patterns were also similar with those of the NMR structure. The cluster–cluster separation in the conformational space indicates that free‐energy barriers separate the clusters at 300°K. The two β‐structural clusters were characterized by different strand–strand hydrogen‐bond (H‐bond) patterns, suggesting that the free‐energy barrier between the two clusters is due to the H‐bond rearrangements.