Simulations and Experiments Delineate Amyloid Fibrilization by Peptides Derived from Glaucoma-Associated Myocilin.

TitleSimulations and Experiments Delineate Amyloid Fibrilization by Peptides Derived from Glaucoma-Associated Myocilin.
Publication TypeJournal Article
Year of Publication2018
AuthorsWang, Y, Gao, Y, Hill, SE, Huard, DJE, Tomlin, MO, Lieberman, RL, Paravastu, AK, Hall, CK
JournalJ Phys Chem B
Volume122
Issue22
Pagination5845-5850
Date Published2018 06 07
ISSN1520-5207
KeywordsAmino Acid Sequence, Amyloid, Cytoskeletal Proteins, Eye Proteins, Glaucoma, Open-Angle, Glycoproteins, Humans, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Peptides, Protein Aggregates, Protein Conformation, beta-Strand
Abstract

Mutant myocilin aggregation is associated with inherited open angle glaucoma, a prevalent optic neuropathy leading to blindness. Comprehension of mutant myocilin aggregation is of fundamental importance to glaucoma pathogenesis and ties glaucoma to amyloid diseases such as Alzheimer's. Here, we probe the aggregation properties of peptides derived from the myocilin olfactomedin domain. Peptides P1 (residues 326-337) and P3 (residues 426-442) were identified previously to form amyloids. Coarse-grained discontinuous molecular dynamics simulations using the PRIME20 force field (DMD/PRIME20) predict that P1 and P3 are aggregation-prone; P1 consistently forms fibrillar aggregates with parallel in-register β-sheets, whereas P3 forms β-sheet-containing aggregates without distinct order. Natural abundance C solid-state NMR spectra validate that aggregated P1 exhibits amyloid signatures and is more homogeneous than aggregated P3. DMD/PRIME20 simulations provide a viable method to predict peptide aggregation propensities and aggregate structure/order which cannot be accessed by bioinformatics or readily attained experimentally.

1
DOI10.1021/acs.jpcb.8b03000
Alternate JournalJ Phys Chem B
PubMed ID29724098
PubMed Central IDPMC6186006
Grant ListR01 AG045703 / AG / NIA NIH HHS / United States
R01 EB006006 / EB / NIBIB NIH HHS / United States
R01 EY021205 / EY / NEI NIH HHS / United States