Self-Assembly of Synthetic and Biological Polymeric Systems of ...

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In vivo, the self-assembly of proteins into highly ordered, β-sheet enriched, fibrillar, insoluble, supramolecular structures known as amyloid fibrils (or amyloid-like fibrils, term referring to protein fibrils that not associated with any disease) is linked to the onset of a growing number of human disorders, including Alzheirmer’s, Parkinson’s, Huntington´s diseases, spongiform encephalopathies, and type II diabetes mellitus. On the other hand, the controlled self- assembly of proteins and peptides into amyloid-like structures may constitute an attractive alternative to develop nanomaterials (106)(107). Amyloid fibrils can be obtained in vitro through different ways by adjusting different external parameters as, for example, pH, ionic strength, and temperature, and cosolute or cosolvent additions. This means that the formation of amyloid-like conformations is not restricted to peptide chains of specific length or having a particular primary or secondary structure; this suggests that the conformational shift into β-sheet rich is energetically preferred. The characterization of the fibrillation process of proteins in vitro has largely been focused on biophysical characterization in order to determine the structure of the fibril, and on biochemical studies to get into the mechanism and kinetics of the process. Also, through techniques such X-ray diffraction, electron microscopy, and solid state NMR spectroscopy we now have a good understanding of the core architecture of individual fibrils too. In general, amyloid fibrils possess distinct physical properties as: i) they are characterized by a cross-β sheet structure, where individual β-strands are perpendicular and each β-sheet is parallel to the fibril axis (Figure 5.4). The X-ray diffraction pattern shows two characteristic reflections at 4.7 Å and 10-11 Å, corresponding to the inter-strand and stacking distances between individual β-sheets, respectively; ii) amyloids bind to histological dyes such as Congo red (CR) and Thioflavin T (ThT). After binding to CR, an apple-green birefringence under cross- polarized light is observed. CR and ThT dyes, however, do not bind to monomeric proteins or peptides. These dyes fluoresce when they bind to β-sheet rich fibrils and are, therefore, useful for spectroscopic monitoring of fibril´s growth and kinetics; iii) under electron microscope (EM), amyloid fibrils appear to be few micrometers long, non-branched filaments, with 7-12 nm diameter. In a majority of cases, amyloids are composed of 2-4 protofilaments that are either helically twisted or laterally associated with each other forming higher order fibrils; iv) amyloids are resistant to heat, wide ranges of pH and proteases (107)-(113). Over the past several years, soluble proteins and protein fragments self-assembled into amyloid aggregates have attracted the interest of researchers from diverse fields. From a 136
molecular medicine viewpoint, protein deposition is an undesired process associated with several human diseases. Hence, different questions must be arisen such as why self- association of a misfolded protein results in organ dysfunction and neurodegeneration?, what are the toxic species?, and whether aggregates of all proteins are toxic or not?. At the molecular level, fundamental research has been directed towards obtaining a rational understanding of the physico-chemical principles underlying protein misfolding and self- assembly. However, given the complexity of the molecular mechanisms driving amyloid aggregation, a frequently used strategy in the field consists of design polypeptide model systems to allow biophysical characterization and the study of their aggregation process (114)- (118). This strategy permits the analysis of the relationship between the amino acid sequence of the polypeptide chain and its structural stability during the conformational transition. Figure 5.4 Schematic representation of an amyloid fibril structure: a) β-strands perpendicular to the fibre axis; the β-sheet structure arises from the hydrogen bonding between lateral side chains of amino acids; b) cross-β diffraction pattern observed in amyloid fibrils. Arrows indicate the positions of the cross-β reflection on the meridian at 4,7 Å (white) and on the equator at 10 Å (black) (112). a) b) Several studies have shown that the destabilization of the polypeptide sequence per se is not enough to bring the self-assembly process up to form amyloid fibrils (119)(120). Additionally, the sudden conformational transition undergone by proteins in their native state to form amyloid fibrils rich in β-sheets is favoured only if the amino acid sequence increase its ability to form β-sheet structures. In most of these systems, the structural transitions from α-helix to β- structures are originated by applying external heat energy. This phenomenon involves a number of relatively weak non-covalent molecular forces: hydrophobic, electrostatic, and 137
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Grupo de Física de Coloides y Pol
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Agradecimientos A mi Familia A mi P
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v List of papers I. Self-assembly p
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2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.
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5.4 5.5 5.3.2 5.5.1 Chapter 6 Kinet
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amiloides de la proteína albúmina
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vesiculares son el resultado de la
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origina debido a condiciones ambien
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con las fibras vecinas más cercana
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Abstract In the present work, we in
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[Au]/[protein] molar ratio and numb
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synthetic polymers are obtained fro
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On the other hand, in terms of chem
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Additionally, to obtain a better kn
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therefore, characteristic of solid
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presence of electrostatic charge in
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Contents 2.1 2.2 2.3 2.4 2.5 2.6 2.
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where w is the meniscus’ weight d
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that they exert little force one on
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This oscillating dipole acts as an
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(APD) and its associated optics (pi
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where r is the distance of the dipo
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When , the former equation can be s
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autocorrelation function (ACF). In
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and, therefore, . The autocorrelati
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A transmission electron microscope
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2.5.- Atomic force microscopy (AFM)
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ecause of the energy loss in the ex
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Figure 2.15. Schematic representati
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ackbone of proteins. Since proteins
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According to classical mechanics, t
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chemical composition, configuration
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2.9.1.- Viscoelasticity Many materi
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where is the total strain rate, whi
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Using equations 2.40 and 2.41 in eq
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scattering process that incoming X-
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maximum intensity of the peak, Imax
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translation of the reciprocal latti
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For a single crystal, the chance to
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excitation; namely, a valance elect
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Figure 2.27. Distinction between si
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microscope, there are two polarized
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In particular, we use SQUID to meas
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are aligned by means of an external
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on the digital profile of a drop im
Page 99 and 100: Laser confocal microscopy. Confocal
Page 101 and 102: Fluorescence spectroscopy. Fluoresc
Page 103: Superconducting quantum interferenc
Page 106 and 107: temperatures, the chains are mixed
Page 108 and 109: e detected by a given method. Therm
Page 110 and 111: subsequently, of their thermodynami
Page 112 and 113: a) O b) H 2C CH 2 O H 2C CH Figure
Page 115: Contents 4.1 4.2 4.3 4.3.1 CHAPTER
Page 118 and 119: 7108 Langmuir, Vol. 24, No. 14, 200
Page 128 and 129: 15704 J. Phys. Chem. C, Vol. 114, N
Page 138 and 139: 4.3.1.- Relevant aspects I. For E12
Page 141 and 142: Contents 5.1 5.2 5.3 5.4 5.5 5.1.1
Page 143 and 144: acids whose lateral side chains cha
Page 145 and 146: adjacent segments of an antiparalle
Page 147 and 148: 5.2.1.- Unfolded state Over the las
Page 149: 5.2.4.- Energy landscape: protein a
Page 153 and 154: shows the typical nucleation-depend
Page 155 and 156: the energy landscape of the aggrega
Page 157: exposed loop region. The secondary
Page 161 and 162: Biophysical Journal Volume 96 March
Page 163 and 164: Fibrillation Pathway of HSA 2355 q
Page 165 and 166: Fibrillation Pathway of HSA 2357 mo
Page 167 and 168: Fibrillation Pathway of HSA 2359 in
Page 169 and 170: Fibrillation Pathway of HSA 2361 Fu
Page 171 and 172: Fibrillation Pathway of HSA 2363 FI
Page 173 and 174: Fibrillation Pathway of HSA 2365 Wh
Page 175 and 176: Fibrillation Pathway of HSA 2367 of
Page 177 and 178: Fibrillation Pathway of HSA 2369 17
Page 179 and 180: Influence of Electrostatic Interact
Page 181 and 182: Fibrillation Process of Human Serum
Page 187: Fibrillation Process of Human Serum
Page 190 and 191: 12392 J. Phys. Chem. B, Vol. 113, N
Page 199 and 200: 5 10 15 20 25 30 35 40 45 Soft Matt
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5 10 15 20 25 r h,app = kT/(6πηD
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5 10 15 20 25 30 35 40 45 50 below,
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5 10 15 20 25 30 55 Figure 3: Selec
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10 15 Soft Matter Cite this: DOI: 1
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5 10 15 Soft Matter Cite this: DOI:
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5 65. L. A. Sikkink, M. Ramirez-Alv
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ions would interact electrostatical
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pubs.acs.org/JPCL Figure 3. (a) Tim
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(54) Almeida, N. L.; Oliveira, C. L
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netospirillum magneticum strain AMB
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One-Dimensional Magnetic Nanowires
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temperatures, and solvent polarity.
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Conclusions The work has two parts:
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equire a highly organized and unsta
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References 1. Hiemenz, Paul C. Poly
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33. Wang, Z. L. HANDBOOK OF MICROSC
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67. Polymers Get Organized. Bucknal
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94. Are there Pathways for Protein
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123. Designing conditions for in vi
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151. SERS-based diagnosis and biode
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