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Protein Science (2007), 16:1596-1608. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Simulation study on the disordered state of an Alzheimer's beta amyloid peptide Abeta(12–36) in water consisting of random-structural, beta-structural, and helical clusters

Jinzen Ikebe1, Narutoshi Kamiya2, Jun-Ichi Ito1, Heisaburo Shindo3, and Junichi Higo1

1 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
2 Clinical Genome Informatics Center, Kobe University, Graduate School of Medicine, Chuo-ku, Kobe 650-0047, Japan
3 School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan

(RECEIVED December 12, 2006; FINAL REVISION April 30, 2007; ACCEPTED May 14, 2007)

The monomeric Alzheimer's beta amyloid peptide, Abeta, 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% beta-structural, and 5% helical. We performed an enhanced conformational sampling (multicanonical molecular dynamics simulation) of a 25-residue segment (residues 12–36) of Abeta 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 beta-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 Abeta 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 beta-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.

Keywords: free-energy landscape; generalized ensemble; multicanonical molecular dynamics; all-atom model; explicit water; fibril formation


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