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

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.