Structure and Aggregation Mechanism of ₂-microglobulin(83-99) peptides Studied by Molecular Dynamics Simulations

¹ Fudan University
² Institut de Biologie Physico-Chimique et Université Paris 7

^* To whom correspondence should be addressed. E-mail: ghwei{at}fudan.edu.cn.

Submitted on January 31, 2007
Revised on February 27, 2007
Accepted on 29 June 2007

	Abstract

Many human neurodegenerative diseases are associated with amyloid fibril formation. The human 99-residue ₂-microglobulin (2m) 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 2m 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 -strands consistent with the results for the monomer, is a possible structure for two 2m(83-89) peptides. Based on our MD-generated dimeric structure, a protofibril model is proposed for the full-length 2m protein.

Key Words: dimer, domain swapping, explicit solvent, potential of mean force, protofibril, replica exchange method

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