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Computational design of new Peptide inhibitors for amyloid Beta (a?) aggregation in Alzheimer's disease: application of a novel methodology.

ABSTRACT: Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major factor creating the compatibility between two amyloid surfaces, making it an important target for the design of amyloid aggregation inhibitors. In this study, a peptide, experimentally proven to bind A?40 fibrils at the GxMxG motif, was mutated by a novel methodology that systematically replaces amino acids with residues that share similar chemical characteristics and subsequently assesses the energetic favorability of these mutations by docking. Successive mutations are combined and reassessed via docking to a desired level of refinement. This methodology is both fast and efficient in providing potential inhibitors. Its efficiency lies in the fact that it does not perform all possible combinations of mutations, therefore decreasing the computational time drastically. The binding free energies of the experimentally studied reference peptide and its three top scoring derivatives were evaluated as a final assessment/valuation. The potential of mean forces (PMFs) were calculated by applying the Jarzynski's equality to results of steered molecular dynamics simulations. For all of the top scoring derivatives, the PMFs showed higher binding free energies than the reference peptide substantiating the usage of the introduced methodology to drug design.

SUBMITTER: Eskici G

PROVIDER: S-EPMC3675214 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Computational design of new Peptide inhibitors for amyloid Beta (aβ) aggregation in Alzheimer's disease: application of a novel methodology.

Eskici Gözde G Gur Mert M

PloS one 20130606 6

Alzheimer's disease is the most common form of dementia. It is a neurodegenerative and incurable disease that is associated with the tight packing of amyloid fibrils. This packing is facilitated by the compatibility of the ridges and grooves on the amyloid surface. The GxMxG motif is the major factor creating the compatibility between two amyloid surfaces, making it an important target for the design of amyloid aggregation inhibitors. In this study, a peptide, experimentally proven to bind Aβ40 ...[more]

PMID: 23762479

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Project description:Nanoscale fibrils formed by amyloid peptides have a polymorphic character, adopting several types of molecular structures in similar growth conditions. As shown by experimental (e.g., solid-state NMR) and computational studies, amyloid fibril polymorphism hinders both the structural characterization of Alzheimer's Aβ amyloid protofilaments and fibrils at a molecular level, as well as the possible applications (e.g., development of drugs or biomarkers) that rely on similar, controlled molecular arrangements of the Aβ peptides in amyloid fibril structures. We have explored the use of several contact potentials for the efficient identification of minimal sequence mutations that could enhance the stability of specific fibril structures while simultaneously destabilizing competing topologies, controlling thus the amount of structural polymorphism in a rational way. We found that different types of contact potentials, while having only partial accuracy on their own, lead to similar results regarding ranking the compatibility of wild-type (WT) and mutated amyloid sequences with different fibril morphologies. This approach allows exhaustive screening and assessment of possible mutations and the identification of minimal consensus mutations that could stabilize fibrils with the desired topology at the expense of other topology types, a prediction that is further validated using atomistic molecular dynamics with explicit water molecules. We apply this two-step multiscale (i.e., residue and atomistic-level) approach to predict and validate mutations that could bias either parallel or antiparallel packing in the core Alzheimer's Aβ9-40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of structural polymorphism in WT Aβ fibrils, our study could also lead to efficient tools for assisting future experimental approaches for amyloid fibril determination, and for the development of biomarkers or drugs aimed at interfering with the stability of amyloid fibrils, as well as for the future design of amyloid fibrils with a controlled (e.g., reduced) level of structural polymorphism.

Dataset Information

Computational design of new Peptide inhibitors for amyloid Beta (a?) aggregation in Alzheimer's disease: application of a novel methodology.

Publications

Computational design of new Peptide inhibitors for amyloid Beta (aβ) aggregation in Alzheimer's disease: application of a novel methodology.

Similar Datasets

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