title: Fast Motions of Key Methyl Groups in Amyloid-β Fibrils.
abstract: Amyloid-β (Aβ) peptide is the major component of plaques found in Alzheimer's disease patients. Using solid-state2H NMR relaxation performed on selectively deuterated methyl groups, we probed the dynamics in the threefold symmetric and twofold symmetric polymorphs of native Aβ as well as the protofibrils of the D23N mutant. Specifically, we investigated the methyl groups of two leucine residues that belong to the hydrophobic core (L17 and L34) as well as M35 residues belonging to the hydrophobic interface between the cross-β subunits, which has been previously found to be water-accessible. Relaxation measurements performed over 310-140 K and two magnetic field strengths provide insights into conformational variability within and between polymorphs. Core packing variations within a single polymorph are similar to what is observed for globular proteins for the core residues, whereas M35 exhibits a larger degree of variability. M35 site is also shown to undergo a solvent-dependent dynamical transition in which slower amplitude motions of methyl axes are activated at high temperature. The motions, modeled as a diffusion of methyl axis, have activation energy by a factor of 2.7 larger in the twofold compared with the threefold polymorph, whereas D23N protofibrils display a value similar to the threefold polymorph. This suggests enhanced flexibility of the hydrophobic interface in the threefold polymorph. This difference is only observed in the hydrated state and is absent in the dry fibrils, highlighting the role of solvent at the cavity. In contrast, the dynamic behavior of the core is hydration-independent.
authors.affiliation: Department of Chemistry, University of Colorado at Denver, Denver, Colorado. Electronic address: liliya.vugmeyster@ucdenver.edu.
authors.forename: Liliya
authors.initials: L
authors.lastname: Vugmeyster
authors.affiliation: Department of Mathematics, University of Colorado at Denver, Denver, Colorado.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Ostrovsky
authors.affiliation: Department of Chemistry, University of Alaska Anchorage, Anchorage, Alaska.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Clark
authors.affiliation: Department of Chemistry, University of Colorado at Denver, Denver, Colorado.
authors.forename: Isaac B
authors.initials: IB
authors.lastname: Falconer
authors.affiliation: Department of Physics, College of William and Mary, Williamsburg, Virginia.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Hoatson
authors.affiliation: Department of Chemistry, Binghamton University, Binghamton, New York.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009068:Movement; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)