Intrinsically disordered proteins are essential for biological processes such as cell signalling, but are also associated to devastating diseases including Alzheimer's disease, Parkinson's disease or type II diabetes. Because of their lack of a stable three-dimensional structure, molecular dynamics simulations are often used to obtain atomistic details that cannot be observed experimentally. The applicability of molecular dynamics simulations depends on the accuracy of the force field chosen to represent the underlying free energy surface of the system. Here, we use replica exchange molecular dynamics simulations to test five modern force fields, OPLS, AMBER99SB, AMBER99SB*ILDN, AMBER99SBILDN-NMR and CHARMM22*, in their ability to model Aβ , an intrinsically disordered peptide associated with Alzheimer's disease, and compare our results to nuclear magnetic resonance (NMR) experimental data. We observe that all force fields except AMBER99SBILDN-NMR successfully reproduce local NMR observables, with CHARMM22* being slightly better than the other force fields.
Protein aggregation into highly structured amyloid fibrils is associated with various diseases including Alzheimer's disease, Parkinson's disease, and type II diabetes. Amyloids can also have normal biological functions and, in the future, could be used as the basis for novel nanoscale materials. However, a full understanding of the physicochemical forces that drive protein aggregation is still lacking. Such understanding is crucial for the development of drugs that can effectively inhibit aberrant amyloid aggregation and for the directed design of functional amyloids. Atomistic simulations can help understand protein aggregation. In particular, atomistic simulations can be used to study the initial formation of toxic oligomers which are hard to characterize experimentally and to understand the difference in aggregation behavior between different amyloidogenic peptides. Here, we review the latest atomistic simulations of protein aggregation, concentrating on amyloidogenic protein fragments, and provide an outlook for the future in this field.
Molecular dynamics
simulations play an essential role in understanding
biomolecular processes such as protein aggregation at temporal and
spatial resolutions which are not attainable by experimental methods.
For a correct modeling of protein aggregation, force fields must accurately
represent molecular interactions. Here, we study the effect of five
different force fields on the oligomer formation of Alzheimer’s
Aβ16–22 peptide and two of its mutants: Aβ16–22(F19V,F20V), which does not form fibrils, and Aβ16–22(F19L) which forms fibrils faster than the wild
type. We observe that while oligomer formation kinetics depends strongly
on the force field, structural properties, such as the most relevant
protein–protein contacts, are similar between them. The oligomer
formation kinetics obtained with different force fields differ more
from each other than the kinetics between aggregating and nonaggregating
peptides simulated with a single force field. We discuss the difficulties
in comparing atomistic simulations of amyloid oligomer formation with
experimental observables.
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