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The β-Strand-Loop-β-Strand Conformation Is Marginally Populated in β₂-Microglobulin (20–41) Peptide in Solution as Revealed by Replica Exchange Molecular Dynamics Simulations

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

^* National Key Surface Physics Laboratory and Department of Physics, Fudan University, Shanghai, China; Laboratoire de Biochimie Théorique, UPR 9080 Centre National de la Recherche Scientifique, Institut de Biologie Physico-Chimique et Université Paris 7, Paris, France; and Département de Physique and Centre de Bioinformatique Robert-Cedergren, Université de Montréal, CP 6128, Montréal, Québec, Canada

Correspondence: Address reprint requests to Guanghong Wei, Tel.: 86-21-55-66-52-31; E-mail: ghwei{at}fudan.edu.cn.

Solid-state NMR study shows that the 22-residue K3 peptide (Ser²⁰-Lys⁴¹) from β₂-microglobulin (β₂m) adopts a β-strand-loop-β-strand conformation in its fibril state. Residue Pro³² has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state of full-length β₂m. To get insights into the structural properties of the K3 peptide, and determine whether the strand-loop-strand conformation is encoded at the monomeric level, we run all-atom explicit solvent replica exchange molecular dynamics on both the cis and trans variants. Our simulations show that the conformational space of the trans- and cis-K3 peptides is very different, with 1% of the sampled conformations in common at room temperature. In addition, both variants display only 0.3–0.5% of the conformations with β-strand-loop-β-strand character. This finding, compared to results on the Alzheimer's Aβ peptide, suggests that the biases toward aggregation leading to the β-strand-loop-β-strand conformation in fibrils are peptide-dependent.