136 Dendritic Alkyl Chains on DNA Cages: A Geometry-Dependent Inter- or Intramolecular “Handshake”

The selective association of hydrophobic sidechains is a strong determinant of protein organization. We have observed a parallel mode of assembly in DNA nanotechnology. Firstly, dendritic DNA amphiphiles (D-DNA) were synthesized (Carneiro, Aldaye, & Sleiman, 2009) comprising an addressable oligonucleotide portion and a hydrophobic alkyl dendron at the 5’ terminus. DNA amphiphiles have gathered interest recently as they can self-assemble in aqueous media to form well defined micelles while also retaining the ability to hybridize to their complement (Kwak & Herrmann, 2011; Patwa, et al. 2011) Two variations of alkyl D-DNA were hybridized to the single-stranded edges of a DNA cube (McLaughlin, et al., 2012). It was found that anisotropic organization of these hydrophobic domains on the 3D scaffold results in a new set of assembly rules, dependent on spatial orientation, number, and chemical identity of the D-DNA on the cubic structure (Edwardson. et al. 2012). When four amphiphiles are organized on one cube face, the hydrophobic residues engage in an intermolecular “handshake” between two cubes, resulting in a dimer. When eight amphiphiles are organized on the top and bottom faces of the cube, they engage in a “handshake” inside the cube. Combining the highly specific recognition of the oligonucleotide sequence with the orthogonal association of hydrophobic moieties can lead to a variety of structures with such diverse applications as membrane anchoring, cell uptake, directed hydrophobic assembly, and encapsulation and release of small molecules.     

Design of a Coiled-Coil-based Model Peptide System to Explore the Fundamentals of Amyloid Fibril Formation

Protein deposition as amyloid fibrils underlies more than twenty severely debilitating human disorders. Interestingly, recent studies suggest that all peptides and proteins possess an intrinsic ability to assemble into amyloid fibrils similar to those observed in disease states. The common properties and characteristics of amyloid aggregates thus offer the prospect that simple model systems can be used to systematically assess the factors that predispose a native protein to form amyloid fibrils and understand the origin and progression of fatal disorders associated with amyloid formation. Here, we report the de novo design of a 17-residue peptide model system, referred to as cc, which forms a protein-like coiled-coil structure under ambient solution conditions but can be easily converted into amyloid fibrils by raising the temperature. Oxidation of methionine residues at selected hydrophobic positions completely abolished amyloid fibril formation of the peptide while not interfering with its coiled-coil structure. This finding indicates that a small number of site-specific hydrophobic interactions can play a major role in the packing of polypeptide chain segments within amyloid fibrils. The simplicity and characteristics of the cc system make it highly suitable for probing molecular details of the assembly of amyloid structures. Abbreviations used for amino acids follow the recommendations of the IUPAC-IUB Commission of Biochemical Nomenclature [Eur. J. Biochem., 138 (1984) 9].