Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events

0571825 - ÚFCH JH 2024 RIV US eng J - Článek v odborném periodiku
Iorio, A. - Timr, Štěpán - Chiodo, L. - Derreumaux, P. - Sterpone, F.
Evolution of large Aβ16–22 aggregates at atomic details and potential of mean force associated to peptide unbinding and fragmentation events.
Proteins-Structure, Function and Bioinformatics. Roč. 91, č. 8 (2023), s. 1152-1162. ISSN 0887-3585. E-ISSN 1097-0134
Institucionální podpora: RVO:61388955
Klíčová slova: amyloid * free energy * molecular dynamics * proto-fibrils
Obor OECD: Physical chemistry
Impakt faktor: 2.9, rok: 2022
Způsob publikování: Omezený přístup

Atomic characterization of large nonfibrillar aggregates of amyloid polypeptides cannot be determined by experimental means. Starting from β-rich aggregates of Y and elongated topologies predicted by coarse-grained simulations and consisting of more than 100 Aβ16–22 peptides, we performed atomistic molecular dynamics (MD), replica exchange with solute scaling (REST2), and umbrella sampling simulations using the CHARMM36m force field in explicit solvent. Here, we explored the dynamics within 3 μs, the free energy landscape, and the potential of mean force associated with either the unbinding of one single peptide in different configurations within the aggregate or fragmentation events of a large number of peptides. Within the time scale of MD and REST2, we find that the aggregates experience slow global conformational plasticity, and remain essentially random coil though we observe slow beta-strand structuring with a dominance of antiparallel beta-sheets over parallel beta-sheets. Enhanced REST2 simulation is able to capture fragmentation events, and the free energy of fragmentation of a large block of peptides is found to be similar to the free energy associated with fibril depolymerization by one chain for longer Aβ sequences.

Trvalý link: https://hdl.handle.net/11104/0342729