The -strand-loop--strand conformation is marginally populated in ₂-microglobulin (20-41) peptide in solution as revealed by replica exchange molecular dynamics simulations

¹ Fudan University
² Universite Paris 7
³ University of Montreal

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

Submitted on November 2, 2007
Revised on December 12, 2007
Accepted on 22 January 2008

	Abstract

Solid-state NMR study shows that the 22-residue K3 peptide (Ser20-Lys41) from ₂-microglobulin (₂m) adopts a -strand-loop--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 ₂m. 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 -strand-loop--strand character. This finding, compared to results on the Alzheimer's A peptide, suggests that the biases toward aggregation leading to the -strand-loop--strand conformation in fibrils are peptide-dependent.

Key Words: Free energy landscape, K3 peptide, dialysis-related amyloidosis, explicit solvent, protofibril, trans and cis isomers