The beta-strand-loop-beta-strand conformation is marginally populated in beta2-microglobulin (20-41) peptide in solution as revealed by replica exchange molecular dynamics simulations

Abstract

Solid-state NMR study shows that the 22-residue K3 peptide (Ser(20)-Lys(41)) from beta(2)-microglobulin (beta(2)m) adopts a beta-strand-loop-beta-strand conformation in its fibril state. Residue Pro(32) has a trans conformation in the fibril state of the peptide, while it adopts a cis conformation in the native state of full-length beta(2)m. 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 beta-strand-loop-beta-strand character. This finding, compared to results on the Alzheimer's Abeta peptide, suggests that the biases toward aggregation leading to the beta-strand-loop-beta-strand conformation in fibrils are peptide-dependent.

FIGURE 1

MD simulations of the trans-K3 and cis-K3 protofibrils. Both models are shown in panel a. The parameters used for comparison are calculated using the four central units of both sheets. (b) Cα-RMSD of the four central chains with respect to the MD-generated trans- and cis-K3 protofibril at 2 ns. Note that the trans structure at 2 ns deviates by 0.14 nm from the solid-state NMR-derived model. (c) Time evolution of the total number of intermolecular main-chain hydrogen bonds. (d) Time evolution of the number of intermolecular side-chain-side-chain atomic contacts between the two groups of residues: Ile³⁵, Val³⁷, Leu³⁹ and Phe²², Asn²⁴, Tyr²⁶, and Phe³⁰.

FIGURE 2

Initial structures and first convergence test on the REMD runs. (a) Initial structures of the trans- and cis-K3 peptides used for REMD simulations. The position of the C-terminus is indicated. (b and c) The REMD-averaged β-strand probability of each residue at 298 K using the time intervals: 22–42 ns, 22–62 ns, and 22–82 ns.

FIGURE 3

Free energy surfaces (in kcal/mol) of the trans- and cis-K3 peptides. Evolution of the cis-K3 free energy surface using the 22–42 (a), 22–62 (b), and 22–82 (c) ns intervals; free energy surface of the trans-K3 peptide using the 22–82 ns interval (d). The two reaction coordinates used are the Cα radius of gyration and the Cα-RMSD with respect to the strand-loop-strand structure in K3 fibril shown in panel e. Pro³² is shown in all-atom representation.

FIGURE 4

Secondary structure probabilities of each residue in the trans- and cis-K3 peptides: (a) β-strand, (b) β-turn, (c) PPII, (d) helix, and (e) coil using the PROSS program.

FIGURE 5

Centers of the first five most-populated structures of the trans- and cis-K3 peptides. Boltzmann population at 298 K is given in parentheses.

FIGURE 6

Probability distribution of the Cα28-Cα33 distance for the trans- and cis-K3 peptides.