title: Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network.
abstract: Most, if not all, peptide- and protein-based hydrogels formed by self-assembly can be characterized as kinetically trapped 3D networks of fibrils. The propensity of disease-associated amyloid-forming peptides and proteins to assemble into polymorphic fibrils suggests that cross-β fibrils comprising hydrogels may also be polymorphic. We use solid-state NMR to determine the molecular and supramolecular structure of MAX1, a de novo designed gel-forming peptide, in its fibrillar state. We find that MAX1 adopts a β-hairpin conformation and self-assembles with high fidelity into a double-layered cross-β structure. Hairpins assemble with an in-register Syn orientation within each β-sheet layer and with an Anti orientation between layers. Surprisingly, although the MAX1 fibril network is kinetically trapped, solid-state NMR data show that fibrils within this network are monomorphic and most likely represent the thermodynamic ground state. Intermolecular interactions not available in alternative structural arrangements apparently dictate this monomorphic behavior.
authors.affiliation: Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702; Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716;
authors.forename: Katelyn
authors.initials: K
authors.lastname: Nagy-Smith
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520.
authors.forename: Eric
authors.initials: E
authors.lastname: Moore
authors.affiliation: Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702;
authors.forename: Joel
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520 robertty@mail.nih.gov.
authors.forename: Robert
authors.initials: R
authors.lastname: Tycko
mesh_terms: D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007553:Isotope Labeling; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary
chemical_list: D010455:Peptides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate
keywords: amyloid; cross-β structure; peptide design; polymorphism; β-hairpin