Dimerization and conformation-related free energy landscapes of dye-tagged amyloid-β12-28linked to FRET experiments.
We have investigated the free energy landscape of Aβ-peptide dimer models in connection to gas-phase FRET experiments. We use a FRET-related distance coordinate and one conformation-related coordinate per monomer for accelerated structural exploration with well-tempered metadynamics in solvent and in vacuo. The free energy profiles indicate that FRET under equilibrium conditions should be significantly affected by the de-solvation upon the transfer of ions to the gas-phase. In contrast, a change in the protonation state is found to be less impacting once de-solvated. Comparing F19P and WT alloforms, for which we measure different FRET efficiencies in the gas-phase, we predict only the relevant structural differences in the solution populations, not under gas-phase equilibrium conditions. This finding supports the hypothesis that the gas-phase action-FRET measurement after ESI operates under non-equilibrium conditions, with a memory of the solution conditions - even for the dimer of this relatively short peptide. The structural differences in solution are rationalized in terms of conformational propensities around residue 19, which show a transition to a poly-proline type of pattern upon mutation to F19P - a difference that gets lost in the gas-phase.
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière Matière, F-69622, Lyon, France. philippe.dugourd@univ-lyon1.fr.
Alexander
http://orcid.org/0000-0002-8812-8548
A
Kulesza
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière Matière, F-69622, Lyon, France. philippe.dugourd@univ-lyon1.fr.
Steven
S
Daly
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière Matière, F-69622, Lyon, France. philippe.dugourd@univ-lyon1.fr.
Philippe
P
Dugourd
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C092395:amyloid beta-protein (12-28)