In solid-phase peptide synthesis (SPPS), the growing peptide chain is anchored at its C-terminus to an insoluble polymer. This allows the sequential addition ...
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13.4.1.4 Beta Sheets
The beta pleated sheet—in short, the beta sheet—is another recurrent structure in proteins; it is noticeably different from the alpha helix. In a beta sheet, the main chain, called the beta strand, is fully extended rather than tightly coiled, and the side chains of adjacent amino acids point in opposite directions. A beta sheet consists of two or more beta strands linked by hydrogen bonds. Adjacent strands that form the beta sheet can either run in opposite directions (antiparallel beta sheet) or in the same direction (parallel beta sheet).
In antiparallel conformation, the CO and NH groups of each amino acid are hydrogen-bonded to the NH and CO groups of the amino acid located in alignment on the adjacent strand. In parallel conformation, the NH group of each amino acid is hydrogen-bonded to the CO group of the amino acid on one side of the adjacent strand’s inline amino, while the CO group is hydrogen-bonded to the NH group of the amino acid located on the other side of the adjacent strand’s inline amino acid. Typically, beta sheets consist of 4 or 5 beta strands where they can be all antiparallel, parallel, or mixed. Beta sheets can be relatively flat or to some extent twisted, which makes them more structurally diverse than alpha helices.
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2.1 Beta sheets
A series of hydrogen bonds between residues in different polypeptide chains or between residues in different sections of a folded polypeptide produced parallel or anti-parallel sheet-like structures. The alternating hydrophobic–hydrophilic residues assembled into sheets with a hydrophobic and hydrophilic face, where two sheets came together to exclude the surrounding aqueous media from the hydrophobic face. Thus, depending on the number of packed sheets, a variety of different hierarchical structural arrays can be designed, including tapes, ribbons, fibrils, and fibres (Fig. 2) [1]. The principle arrangement of amino acids to form beta sheet nanoribbons is alternating placement of charged (or polar) and hydrophobic amino acids to promote tailored hydrogen bonding between hydrogen donors and acceptors within the peptide. Furthermore, peptide structures that contained alkyl chains, 9-fluorenylmethyloxycarbonyl (Fmoc) peptides, and cyclic peptides (e.g. cyclo[(D-Ala-Glu-D-Ala-Gln)2]), have the ability to form beta sheets through hydrophobic collapse and stacking on top of each other, thereby adopting a low energy, ring shaped conformation resulting in nanotube formation [4]. Mechanical properties of self-assembled beta sheets can be controlled by adjusting the molar ratio of enantiomeric peptides (e.g. VDPPT) as a design tool. The use of chirality in peptide design has been shown to greatly improve the stability of peptide scaffolds against enzymatic degradation [56,57].
Fig. 2. Schematic representation of peptides that form beta sheets and the self-assembled structures that can be formed. A: a peptide sequence with alternating hydrophilic (X) and hydrophobic (Y) residues. B: assembly of the beta sheet peptides into a molecule that contains both a hydrophilic and hydrophobic face. C: self-assembly of the beta sheet forming peptide into a tape, ribbon, fibril, and fibre based on their packing density [65].
(Reproduced and adapted with permission from Elsevier.)Moreover, Bombyx mori silk fibroin—a natural resource and an alanine glycine (AG)-rich polypeptide—was shown to form extended beta strands. The alanine glycine-rich peptides inspired synthetic polypeptides that contained a repetitive sequence of [(AG)xEG]n (where x was 3–6 amino acids long) that was attributed to the formation of these extended beta sheets [58]. Peptides that form beta sheets have applications in drug delivery as nanowires, nanofibers or hydrogel scaffolds, where the ability to encapsulate hydrophobic guest molecules, such as pyrene or Nile red, between the two beta sheets enhanced their cell-penetration and uptake [59–64]. In comparison with spherical particles, beta sheet filamentous particles (including cylindrical micelles, nanotubes, nanoribbons, and nanobelts) were able to improve drug bioavailability by increasing circulation times and the maximum tolerable dose, achieving a higher tumour cell apoptosis, delayed clearance of the drug by the liver and spleen, and minimal interactions with serum proteins due to their charge-neutral surface [61].
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Beta-sheets in protein design
Beta-strands are frequent structural elements in proteins, albeit commonly regarded as less amenable to design due to their less straightforward orthogonality rules and tendency to aggregate, if compared to α-helices. Nevertheless, recent examples of protein design showed the successful implementation of β-elements in de novo structures, paving the way to a more broad use of β-sheet in novel proteins. Beta-strands are by definition involved in mid-range to long-range interactions and are frequently present in intertwined topologies, thus serving as optimal candidates for designing complex protein folds.
Marcos et al. recently introduced the design of all-β topologies characterized by high contact order [43•]. Via parametric evaluation of the backbones from a dataset of natural β-sheet proteins, they individuated a correlation between side-chain orientation and local backbone geometry in the loops connecting the β-filaments of jellyroll folds. Length of β-filaments, as well as their side chain orientation and curvature were also taken into consideration allowing the design of a de novo jellyroll protein in high accordance to the initial model (Figure 3a). Parametrically designing curved and non-regular β-sheet-containing proteins remains a challenging task in protein design, yet also in this case few recent examples of successful designs clarified some of the folding rules; showing for instance the importance of incorporating symmetry breaking element in β-filaments in order to establish contiguous hydrogen bond networks and remove structural constrains [44,45••] (Figure 3b–c).
Figure 3. De novo designed β-sheet proteins.
(a) Jellyroll fold designed de novo by observing the topological constrains in natural analogous folds [43•] (PBD: 6E5C). (b) Curved α-β protein showing a bulge in the β-sheet layer [44] (PDB: 5TPJ). (c) Beta-barrel BB1, consisting of the first example of a completely de novo reconstruction of this topology [45••] (PDB: 6D0T). The models are colored based on rainbow coloring scheme, with N-terminal of the protein in blue and C-terminal in red.
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β-sheet secondary structure of peptides
β-sheet is another significant secondary structure of protein consisting of beta strands (also β-strand) linked laterally by several hydrogen bonds in the backbone, forming a generally zig-zag and twisted pleated sheet. Most beta sheet conformation exists in amyloid peptides, the aggregation of which will result in peptide fibrillation that is closely related to the pathogenesis of some degenerative diseases, such as Alzheimer’s disease [71,72], Type II diabetes, etc [73]. In recent years, some strategies have been developed to construct 2D self-assembled nanostructure by modulating and enhancing the specific interactions between peptides with β-sheet secondary structure.
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β-Sheet
β-Sheets are the most common natural motifs that can be used in driving the self-assembly of peptides. β-Sheets consist of sequences that possess alternating hydrophobic and hydrophilic amino acids, providing the peptide backbone an amphiphilic property that directs formation of β-sheets. Fishwick et al. proposed that the P11-II peptide sequence QQRFQWQFEQQ and its derivatives form twisted β-sheet tapes, naturally reinforced by the amphiphilic nature of the sequence. These β-sheet tapes are triggered to form hydrogels by screening the charges between fibers [15].
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The β-sheet is the second common form of regular secondary structure in proteins consisting of β-strands, which are connected laterally by three or more hydrogen bonds, forming a twisted, pleated sheet. A β-sheet unit has extensive hydrogen bonding between the carbonyl oxygen of an amino acid in one strand and the nitrogen of a second amino acid in another strand. The hydrogen bonding, along with the contribution of hydrophobic effects, stabilizes the β-sheets. β-Sheets can be either parallel, two β-sheet units aligned in the same direction from one terminus to the other, or antiparallel, the units aligned in the opposite direction. Recent research has focused on the role of β-sheet-rich fibrillar structures in neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jakob's diseases in humans, and bovine spongiform encelophalopathy and scrapie in animals [51–57]. The ability to design β-sheet nanostructures to self-assemble into amyloid-like fibrils, where the fundamental unit of amyloid fibrils is found to be a steric zipper formed by two tightly interdigitated β-sheets [58], has helped researchers to understand the folding and pathogenesis mechanisms better, and enabled the generation of new biomaterials with interesting properties [59–64].
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The prediction of the sequences shows the presence of at least two close strand regions (beta-sheet regions) in which the amino acid chain is folded (yellow arrows in Fig. 12). A region similar to the core box, with high homology and containing strand regions, is present in high-sulfur proteins (underlined in Fig. 13). This region probably interacts in an orderly 3D conformation with similar regions of other beta-keratins (monomers) to produce the framework of the filamentous form of beta-keratin (the polymer; see Fraser et al., 1972; Gregg and Rogers, 1986; Brush, 1993; Fraser and Parry, 1996; Fig. 12E). The beta-pleated region has been found in all reptilian and avian beta-keratins so far sequenced, indicating that it is a basic structural motif present in these self-assembling proteins.
Fig. 13. Prediction of the secondary structure, molecular weight (kDa) and isoelectric point (pI) of four cysteine-rich proteins of different molecular weight from G. gekko, showing the presence of the core box sequences (underlined) where 2–3 beta-folds (arrows) are present (see Hallahan et al., 2008, and the GenBank database for these proteins). Ge-cprp-x, gecko cysteine–proline-rich protein-x.
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5.1.2.1 β-Sheets
β-sheet structures contain parallel and antiparallel strands with an extended backbone, that permits hydrogen bonding between the backbone amides and carbonyls. The arrangement of C and N-termini of the beta strands (on the same side-parallel and alternate sides-antiparallel) has an important impact on the H-bonding, side chains, and orientations in the structure. From the literature studies, β-Sheets forming peptides both natural or synthesized ones are known to dominate α-helical peptides as they can form long-range interactions. β-sheets, well known for their ability to form ordered amyloid fibrils in amyloid diseases, was initially identified by Pauling, Corey, and others in the 1950s (Pauling & Corey, 1951). It was Zhang in 1900, who first demonstrated the use of β-sheets in the design of materials (Zhang, Holmes, Lockshin, & Rich, 1993). Self-assembled β-sheets formed a hierarchy of structures such as tapes, ribbons, fibrils, and fibers (Aggeli et al., 2001). Studies were reported on the systematic variation of peptide sequences containing a different number of hydrophobic residues, and their position helped in finding the key features like the critical concentration of aggregation in the peptides (Caplan, Schwartzfarb, Zhang, Kamm, & Lauffenburger, 2002). The hypothesis of aromatic stacking in the β-sheets of amyloid proteins (Chiti and Dobson, 2006), further inspired the design of a series of β-sheets forming peptides interacting through aromatic π-π stacking. However, the main challenge faced in designing a self-assembled system mediated through β-sheets is to control the assembly to form a uniform and reproducible architecture.
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The predicted beta strands 275VQII278 and 306VQIVY310 are potentially the most important structural elements for tau's ability to self-aggregate into ordered structures. These sequences have been shown to be capable of forming filamentous structures in the absence of the rest of the molecule and likely represent the core structural elements for filament elongation [9,34,35]. These sequences have also been shown to adopt a beta strand conformation upon aggregation by several methods, including FTIR, CD, and X-ray diffraction [9,34,35]. These beta strands would have a somewhat amphipathic nature (Fig. 3A and B), with several hydrophobic residues on one face, with a relatively polar face opposite. It has been previously suggested that this amphipathic nature could account for the strong association of these structural elements that lead to their aggregation [9,34]. In this situation, the amphipathic strands would form horizontal sheets that could then stack on top of one another to propagate the filament growth (Fig. 3C and D).
Fig. 3. Potential amphipathic beta strands formed by 274KVQIINK280 and 305SVQIVYK311. The sequences (A) 274KVQIINK280 and (B) 305SVQIVYK311 are depicted as beta strands with charged amino acids depicted in red, noncharged polar amino acids depicted in blue, and hydrophobic residues depicted in green. These amphipathic helices could potentially form stable beta sheets that stack in the vertical plane due to the alternating hydrophobic/polar interactions of the beta strands, forming structures that could be considered to be similar to “protofilaments”. D) The beta strands in “protofilaments” could then interact laterally to form a tau filament. The amphipathicity of the beta strands could also play a role in the stabilization of “protofilament” interactions. A similar schematic for tau polymerization via this mechanism appeared in von Bergen et. al. [34].
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β-Sheet
The TBP represents one of the few protein families that use an extended β-sheet to bind target DNA. TBP is a transcription factor that recognizes and binds to a TATA-box sequence that is extremely A/T-rich. TBP consists of two domains separated by a concave anti-parallel 10-stranded β-sheet which covers and binds at the DNA minor-groove (shown in Figure 2(f)). This interaction is facilitated by two phenylalanine residues from each β-sheet edge which intercalate into the DNA minor groove. This intercalation causes a broad opening of the minor groove and large-scale distortion of the DNA which can then accommodate the twisted structure of the large sheet. Sequence specificity is achieved through contacts between residues on the β-sheet surface and the edges of newly accessible base pairs and through the sequence-dependent deformability of the A/T-rich TATA-box sequence.
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This is typically the highest-risk step. The time between amino acid activation and incorporation into the growing chain determines how long reactive intermediates are present. Longer activation times and higher temperatures increase the likelihood of oxazolone formation.
Evidence grade: retrospective cohort; confounding possible.(All responses are research-focused and do not imply human or animal application.)
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