Nonproductive Binding Modes as a Prominent Feature of Aß40 Fiber Elongation: Insights from Molecular Dynamics Simulation.
J Chem Inf Model
; 58(8): 1576-1586, 2018 08 27.
Article
en En
| MEDLINE
| ID: mdl-30047732
ABSTRACT
The formation of amyloid fibers has been implicated in a number of neurodegenerative diseases. The growth of amyloid fibers is strongly thermodynamically favorable, but kinetic traps exist where the incoming monomer binds in an incompatible conformation that blocks further elongation. Unfortunately, this process is difficult to follow experimentally at the atomic level. It is also too complex to simulate in full detail and to date has been explored either through coarse-grained simulations, which may miss many important interactions, or full atomic simulations, in which the incoming peptide is constrained to be near the ideal fiber geometry. Here we use an alternate approach starting from a docked complex in which the monomer is from an experimental NMR structure of one of the major conformations in the unbound ensemble, a largely unstructured peptide with the central hydrophobic region in a 310 helix. A 1000 ns full atomic simulation in explicit solvent shows the formation of a metastable intermediate by sequential, concerted movements of both the fiber and the monomer. A Markov state model shows that the unfolded monomer is trapped at the end of the fiber in a set of interconverting antiparallel ß-hairpin conformations. The simulation here may serve as a model for the binding of other non-ß-sheet conformations to amyloid fibers.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Péptidos beta-Amiloides
/
Simulación de Dinámica Molecular
/
Amiloide
Tipo de estudio:
Health_economic_evaluation
Límite:
Humans
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
India