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Structure and Aggregation Mechanism of β₂-Microglobulin (83–99) Peptides Studied by Molecular Dynamics Simulations

Chungwen Liang ^*, Philippe Derreumaux  and Guanghong Wei ^*

^* National Key Surface Physics Laboratory and Department of Physics, Fudan University, Shanghai, China; and Laboratoire de Biochimie Théorique, UPR 9080, Centre National de la Recherche Scientifique, Institut de Biologie Physico-Chimique et Université Paris 7, Paris, France

Correspondence: Address reprint requests to G. Wei, Tel.: 86-21-55-66-5231; E-mail: ghwei{at}fudan.edu.cn.

Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue β₂-microglobulin (β2m) is one of the most intensively studied amyloid-forming proteins. Recent studies show that the C-terminal fragments 72–99, 83–89, and 91–96 form by themselves amyloid fibrils in vitro and play a significant role in fibrillization of the full-length β2m protein under acidic pH conditions. In this work, we have studied the equilibrium structures of the 17-residue fragment 83–99 in solution, and investigated its dimerization process by multiple molecular dynamics simulations. We find that an intertwined dimer, with the positions of the β-strands consistent with the results for the monomer, is a possible structure for two β2m(83–89) peptides. Based on our molecular-dynamics-generated dimeric structure, a protofibril model is proposed for the full-length β2m protein.

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