Category: Partially crystalline order in biological macromolecules

M. Baumann¹, M. Gopalswamy¹, J. Adler², B. Voigt¹, D. Huster²,
and J. Balbach¹

¹Institute of Physics, Biophysics, University Halle-Wittenberg, Germany
²Institute for Medical Physics and Biophysics, University Leipzig, Germany

Amyloids are well ordered protein aggregates involved in many functional and pathogenic processes of life. Various structural models of the molecular architecture of amyloids have been derived in the last decade mainly driven by advances in solid state NMR. This talk will summarize our NMR efforts to study not only structural features of mature fibrils but the amyloid formation mechanism. Two systems will be covered: the Alzheimer peptide Aβ(1-40) and variants as well as the human parathyroid hormone PTH(1-84). For Aβ(1-40) we show that backbone hydrogen bonds are the main driving force for fibril structure formation overwriting side chain effect and buffer conditions [1,2]. Additionally, we show that morphological properties of fibril seeds do not necessarily propagate towards the growing fibril [3]. Several molecular observations during the formation of PTH(1-84) fibrils will be presented [4] to classify them as functional amyloids and possible storage form of the hormone.Amyloids are well ordered protein aggregates involved in many functional and pathogenic processes of life. Various structural models of the molecular architecture of amyloids have been derived in the last decade mainly driven by advances in solid state NMR. This talk will summarize our NMR efforts to study not only structural features of mature fibrils but the amyloid formation mechanism. Two systems will be covered: the Alzheimer peptide Aβ(1-40) and variants as well as the human parathyroid hormone PTH(1-84). For Aβ(1-40) we show that backbone hydrogen bonds are the main driving force for fibril structure formation overwriting side chain effect and buffer conditions [1,2]. Additionally, we show that morphological properties of fibril seeds do not necessarily propagate towards the growing fibril [3]. Several molecular observations during the formation of PTH(1-84) fibrils will be presented [4] to classify them as functional amyloids and possible storage form of the hormone.

References
[1] M. Garvey, M. Baumann, M. Wulff, M. Fändrich, J. Balbach et al., Amyloid 23, 76 (2016). (link)
[2] J. Adler, M. Baumann, B. Voigt, H. A. Scheidt, D. Bhowmik, T. Haupl, B. Abel, P. K. Madhu, J. Balbach, S. Maiti, and D. Huster, ChemPhysChem 17, 2744 (2016). (link)
[3] M. Wulff, M. Baumann, J. Balbach, M. Fändrich et al., Angew. Chemie Int. Ed. 55, 5081 (2016). (link)
[4] M. Gopalswamy, A. Kumar, J. Adler, M. Baumann, M. Henze, S. T. Kumar, M. Fändrich, H. A. Scheidt, D. Huster, and J. Balbach, Biochim. Biophys. Acta 1854, 249 (2015). (link)

N. Bernhardt, W. Xi, and Ulrich H.E. Hansmann

Dept. of Chemistry & Biochemistry, University of Oklahoma, Norman, OK 73019, USA

The primary toxic agents in Alzheimer’s disease appear to be small soluble oligomers formed either on-pathway or off-pathway to the assembly of the insoluble fibrils that are one hallmark of the illness. Hence, it is important to understand how the equilibrium between the polymorphous fibrils and oligomers is shifted by mutations, changing environmental conditions, or in the presence of prion-like amyloid strains. These processes are difficult to probe in experiments, and detailed experimental structures exist only for the amyloid fibrils. Most of these fibrils are built from Aβ_1-40 peptides that form U-shaped β-hairpins. For the more toxic Aβ_1-42 one observes in addition a S-shaped triple-β-stranded motif that cannot be formed by Aβ_1-40 peptides. We argue that the higher toxicity of this species is related to the ability of Aβ_1-42 to form this motif. In order to test this hypothesis we show that the S-shaped Aβ_1-42 peptides assemble into oligomer and fibril structures that cannot be build by U-shaped chains. Stability of these aggregates and inter-conversion between them is studied by regular and enhanced molecular dynamics techniques. These simulations allow us to propose a mechanism for formation and propagation of Aβ_1-42 amyloids.

References
[1] N.A. Bernhardt, W. Xi, W. Wang and U.H.E. Hansmann, J. Chem. Theor. Comp. 12, 5656 (2016). (link)
[2] W. Xi, W.Wang, G.L. Abbott and U.H.E. Hansmann, J. Phys. Chem. B, 120, 4548 (2016). (link)
[3] H. Zhang, W. Xi, U.H.E. Hansmann and Y. Wei, J. Chem. Theor. Comp., (DOI: 10.1021/acs.jctc.7b00383). (link)
[4] W. Xi and U.H.E. Hansmann, Scientific Report, 7, 6588 (2017) (link)

A. M. Anton and F. Kremer

Peter Debye Institute for Soft Matter Physics, University of Leipzig, Linnéstr. 5, 04103 Leipzig

Spider dragline silk exhibits remarkable characteristics such as exceptional toughness arising from high tensile strength combined with great elasticity. Its mechanical properties are based on a refined architecture on the molecular scale: Proteins with highly repetitive core motifs aggregate into nanometer-sized crystals, rich non alanine in β-sheet secondary structure, surrounded by an amorphous, glycine rich matrix. During spinning the less ordered parts are elongated, which orients both substructures and gives rise to an inherent non-equilibrium state. Thus, external stress is directly transferred to the crystallites, as demonstrated by FTIR experiments in combination with uniaxial stress [1] or hydrostatic pressure [2].Spider dragline silk exhibits remarkable characteristics such as exceptional toughness arising from high tensile strength combined with great elasticity. Its mechanical properties are based on a refined architecture on the molecular scale: Proteins with highly repetitive core motifs aggregate into nanometer-sized crystals, rich non alanine in β sheet secondary structure, surrounded by an amorphous, glycine rich matrix. During spinning the less ordered parts are elongated, which orients both substructures and gives rise to an inherent non-equilibrium state. Thus, external stress is directly transferred to the crystallites, as demonstrated by FTIR experiments in combination with uniaxial stress [1] or hydrostatic pressure [2].Even though the protein structure has been thoroughly studied, until recently it was not possible to artificially re-create this exceptional (morphological and functional) architecture. We show that wet spinning of a novel biomimetic protein results in fibers with a similar nanostructure as the natural template. However, only post spinning strain induces a microscopic non-equilibrium that gives rise to a similar mechanism of energy dissipation as in natural spider silk and comparable macroscopic toughness [3,4].

References
[1] P. Papadopoulos, J. Sölter, and F. Kremer, Eur. Phys. J. E 24, 193 (2007). (link)
[2] A. M. Anton, C. Kuntscher, F. Kremer et al., Macromolecules 46, 4919 (2013). (link)
[3] A. Heidebrecht, T. Scheibel et al., Adv. Mater. 27, 2189 (2015). (link)
[4] A. M. Anton, M. Beiner, T. Scheibel, F. Kremer et al, manuscript submitted