Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide

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Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide. / Cohen, Samuel I.A.; Cukalevski, Risto; Michaels, Thomas C.T.; Šarić, A.; Törnquist, Mattias; Vendruscolo, Michele; Dobson, Christopher M.; Buell, Alexander K.; Knowles, Tuomas P.J.; Linse, Sara.

I: Nature Chemistry, Vol. 10, Nr. 5, 01.05.2018, s. 523-531.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Cohen, SIA, Cukalevski, R, Michaels, TCT, Šarić, A, Törnquist, M, Vendruscolo, M, Dobson, CM, Buell, AK, Knowles, TPJ & Linse, S 2018, 'Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide', Nature Chemistry, vol. 10, nr. 5, s. 523-531. https://doi.org/10.1038/s41557-018-0023-x

APA

CBE

Cohen SIA, Cukalevski R, Michaels TCT, Šarić A, Törnquist M, Vendruscolo M, Dobson CM, Buell AK, Knowles TPJ, Linse S. 2018. Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide. Nature Chemistry. 10(5):523-531. https://doi.org/10.1038/s41557-018-0023-x

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Author

Cohen, Samuel I.A. ; Cukalevski, Risto ; Michaels, Thomas C.T. ; Šarić, A. ; Törnquist, Mattias ; Vendruscolo, Michele ; Dobson, Christopher M. ; Buell, Alexander K. ; Knowles, Tuomas P.J. ; Linse, Sara. / Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide. I: Nature Chemistry. 2018 ; Vol. 10, Nr. 5. s. 523-531.

RIS

TY - JOUR

T1 - Distinct thermodynamic signatures of oligomer generation in the aggregation of the amyloid-β peptide

AU - Cohen, Samuel I.A.

AU - Cukalevski, Risto

AU - Michaels, Thomas C.T.

AU - Šarić, A.

AU - Törnquist, Mattias

AU - Vendruscolo, Michele

AU - Dobson, Christopher M.

AU - Buell, Alexander K.

AU - Knowles, Tuomas P.J.

AU - Linse, Sara

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Mapping free-energy landscapes has proved to be a powerful tool for studying reaction mechanisms. Many complex biomolecular assembly processes, however, have remained challenging to access using this approach, including the aggregation of peptides and proteins into amyloid fibrils implicated in a range of disorders. Here, we generalize the strategy used to probe free-energy landscapes in protein folding to determine the activation energies and entropies that characterize each of the molecular steps in the aggregation of the amyloid-β peptide (Aβ42), which is associated with Alzheimer's disease. Our results reveal that interactions between monomeric Aβ42 and amyloid fibrils during fibril-dependent secondary nucleation fundamentally reverse the thermodynamic signature of this process relative to primary nucleation, even though both processes generate aggregates from soluble peptides. By mapping the energetic and entropic contributions along the reaction trajectories, we show that the catalytic efficiency of Aβ42 fibril surfaces results from the enthalpic stabilization of adsorbing peptides in conformations amenable to nucleation, resulting in a dramatic lowering of the activation energy for nucleation.

AB - Mapping free-energy landscapes has proved to be a powerful tool for studying reaction mechanisms. Many complex biomolecular assembly processes, however, have remained challenging to access using this approach, including the aggregation of peptides and proteins into amyloid fibrils implicated in a range of disorders. Here, we generalize the strategy used to probe free-energy landscapes in protein folding to determine the activation energies and entropies that characterize each of the molecular steps in the aggregation of the amyloid-β peptide (Aβ42), which is associated with Alzheimer's disease. Our results reveal that interactions between monomeric Aβ42 and amyloid fibrils during fibril-dependent secondary nucleation fundamentally reverse the thermodynamic signature of this process relative to primary nucleation, even though both processes generate aggregates from soluble peptides. By mapping the energetic and entropic contributions along the reaction trajectories, we show that the catalytic efficiency of Aβ42 fibril surfaces results from the enthalpic stabilization of adsorbing peptides in conformations amenable to nucleation, resulting in a dramatic lowering of the activation energy for nucleation.

U2 - 10.1038/s41557-018-0023-x

DO - 10.1038/s41557-018-0023-x

M3 - Article

VL - 10

SP - 523

EP - 531

JO - Nature Chemistry

T2 - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

IS - 5

ER -