Peptide-Dendron Hybrids that Adopt Sequence-Encoded ß-Sheet Conformations.

Rational design rules for programming hierarchical organization and function through mutations of monomers in sequence-defined polymers can accelerate the development of novel polymeric and supramolecular materials. Our strategy for designing peptide-dendron hybrids that adopt predictable secondary and quaternary structures in bulk is based on patterning the sites at which dendrons are conjugated to short peptides. To validate this approach, we have designed and characterized a series of ß-sheet-forming peptide-dendron hybrids. Spectroscopic studies of the hybrids in films reveal that the peptide portion of the hybrids adopts the intended secondary structure.

Hexagonally Ordered Arrays of α-Helical Bundles Formed from Peptide-Dendron Hybrids.

Combining monodisperse building blocks that have distinct folding properties serves as a modular strategy for controlling structural complexity in hierarchically organized materials. We combine an α-helical bundle-forming peptide with self-assembling dendrons to better control the arrangement of functional groups within cylindrical nanostructures. Site-specific grafting of dendrons to amino acid residues on the exterior of the α-helical bundle yields monodisperse macromolecules with programmable folding and self-assembly properties. The resulting hybrid biomaterials form thermotropic columnar hexagonal mesophases in which the peptides adopt an α-helical conformation. Bundling of the α-helical peptides accompanies self-assembly of the peptide-dendron hybrids into cylindrical nanostructures. The bundle stoichiometry in the mesophase agrees well with the size found in solution for α-helical bundles of peptides with a similar amino acid sequence.

Synthesis and Self-Assembly of Bundle-Forming α-Helical Peptide-Dendron Hybrids.

Dendronized helix bundle assemblies combine the sequence diversity and folding properties of proteins with the tailored physical properties of dendrimers. Assembly of peptide-dendron hybrids into α-helical bundles encapsulates the helix bundle motif in a dendritic sheath that will allow the functional, protein-like domain to be transplanted to nonbiological environments. A bioorthogonal graft-to synthetic strategy for preparing helix bundle-forming peptide-dendron hybrids is described herein for hybrids 1a, 1b, and 2. Titration experiments monitored by circular dichroism spectroscopy support our self-assembly model for how the peptide-dendron hybrids self-assemble into α-helical bundles with the dendrons on outside of the bundle.

Bundle-forming α-helical peptide-dendron hybrid.

Peptides and dendrons are enticing building blocks from which to construct hybrid macromolecules because each can be prepared as monodisperse and sequence defined materials. Folding and assembly properties designed into the amino acid sequence of a peptide-dendron hybrid manifest in the formation of a dendronized bundle of α-helices.

Efficient Syntheses of Star-Branched, Multifunctional Mesogens.

Star-branched molecular architectures lend themselves to convergent synthesis strategies for creating materials that combine three or more functional modalities, but these approaches require a core moiety with several reactive groups that are orthogonal to one another. The direct synthesis of three-arm, star-branched mesogens has been investigated via the Passerini three-component reaction to demonstrate how multicomponent reactions circumvent the need to identify and synthesize specialized branched core molecules.

Azide-rich peptides via an on-resin diazotransfer reaction.

Azide-containing amino acids are valuable building blocks in peptide chemistry, because azides are robust partners in several bioorthogonal reactions. Replacing polar amino acids with apolar, azide-containing amino acids in solid-phase peptide synthesis can be tricky, especially when multiple azide residues are to be introduced in the amino acid sequence. We present a strategy for effectively incorporating multiple azide-containing residues site-specifically.

Enhanced reactivity of dendrons in the Passerini three-component reaction.

Polymer chemistry has embraced multicomponent reactions for synthesizing multifunctional materials, including structurally perfect multimodal dendrimers. An unexpected substituent effect dramatically shortens the time required for the convergent synthesis of dendrimers via the Passerini three-component reaction.

Template-constrained cyclic sulfopeptide HIV-1 entry inhibitors.

Template-constrained cyclic sulfopeptides that inhibit HIV-1 entry were rationally designed based on a loop from monoclonal antibody (mAb) 412d. A focused set of sulfopeptides was synthesized using Fmoc-Tyr(SO3DCV)-OH (DCV = 2,2-dichlorovinyl). Three cyclic sulfopeptides that inhibit entry of HIV-1 and complement the activity of known CCR5 antagonists were identified.

Convergent synthesis of dendrimers via the Passerini three-component reaction.

Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers.

Induced helical backbone conformations of self-organizable dendronized polymers.

Control of function through the primary structure of a molecule presents a significant challenge with valuable rewards for nanoscience. Dendritic building blocks encoded with information that defines their three-dimensional shape (e.g., flat-tapered or conical) and how they associate with each other are referred to as self-assembling dendrons. Self-organizable dendronized polymers possess a flat-tapered or conical self-assembling dendritic side chain on each repeat unit of a linear polymer backbone. When appended to a covalent polymer, the self-assembling dendrons direct a folding process (i.e., intramolecular self-assembly). Alternatively, intermolecular self-assembly of dendrons mediated by noncovalent interactions between apex groups can generate a supramolecular polymer backbone. Self-organization, as we refer to it, is the spontaneous formation of periodic and quasiperiodic arrays from supramolecular elements. Covalent and supramolecular polymers jacketed with self-assembling dendrons self-organize. The arrays are most often comprised of cylindrical or spherical objects. The shape of the object is determined by the primary structure of the dendronized polymer: the structure of the self-assembling dendron and the length of the polymer backbone. It is therefore possible to predictably generate building blocks for single-molecule nanotechnologies or arrays of supramolecules for bottom-up self-assembly. We exploit the self-organization of polymers jacketed with self-assembling dendrons to elucidate how primary structure determines the adopted conformation and fold (i.e., secondary and tertiary structure), how the supramolecules associate (i.e., quaternary structure), and their resulting functions. A combination of experimental techniques is employed to interrogate the primary, secondary, tertiary, and quaternary structure of the self-organizable dendronized polymers. We refer to the process by which we interpolate between the various levels of structural information to rationalize function as retrostructural analysis. Retrostructural analysis validates our hypothesis that the self-assembling dendrons induce a helical backbone conformation in cylindrical self-organizable dendronized polymers. This helical conformation mediates unprecedented functions. Self-organizable dendronized polymers have emerged as powerful building blocks for nanoscience by virtue of their dimensions and ability to self-organize. Discrete cylindrical and spherical structures with well-defined dimensions can be visualized and manipulated individually. More importantly, they provide a robust framework for elucidating functions available only at the nanoscale. This Account will highlight structures and functions generated from self-organizable dendronized polymers that enable integration of the nanoworld with its macroscopic universe. Emphasis is placed on those structures and functions derived from the induced helical backbone conformation of cylindrical self-organizable dendronized polymers.

Nanomechanical function from self-organizable dendronized helical polyphenylacetylenes.

Self-organizable dendronized helical polymers provide a suitable architecture for constructing molecular nanomachines capable of expressing their motions at macroscopic length scales. Nanomechanical function is demonstrated by a library of self-organized helical dendronized cis-transoidal polyphenylacetylenes ( cis-PPAs) that possess a first-order phase transition from a hexagonal columnar lattice with internal order (varphi h (io)) to a hexagonal columnar liquid crystal phase (varphi h). These polymers can function as nanomechanical actuators. When extruded as fibers, the self-organizable dendronized helical cis-PPAs form oriented bundles. Such fibers have been shown capable of work by displacing objects up to 250-times their mass. The helical cis-PPA backbone undergoes reversible extension and contraction on a single molecule length scale resulting from cisoid-to-transoid conformational isomerization of the cis-PPA. Furthermore, we clarify supramolecular structural properties necessary for the observed nanomechanical function.

Supramolecular structural diversity among first-generation hybrid dendrimers and twin dendrons.

Hybrid dendrimers, obtained by complete monofunctionalization of the peripheral amines of a "zero-generation" polyethyleneimine dendrimer, provide structurally diverse lamellar, columnar, and cubic self-organized lattices that are less readily available from other modified dendritic structures. The reaction of tris(2-aminoethyl)amine (TREN) with 4-dodecyloxybenzimidazolide provides only the corresponding zero-generation TREN dendrimer. From the mixture of tri- and disubstituted TREN derivatives obtained from first-generation self-assembling dendritic imidazolides, the hybrid dendrimer and a twin dendron could be separated, purified, and characterized. The hybrid dendrimers display smectic, columnar hexagonal (Phi(h)), and cubic (Pm_3n) lattices. The TREN twin dendrons, on which only two peripheral amines have been acylated, exhibit centered-rectangular columnar (Phi(r-c)), Phi(h), and Pm_3n lattices. The existence of a thermoreversible Phi(h)-to-Pm_3n phase transition in the first-generation hybrid dendrimers and twin dendrons is exploited to elucidate an epitaxial relationship between the two mesophases. We postulate a mechanism by which the transition proceeds. The thermoreversible Phi(h)-to-Pm_3n phase change is accompanied by optical property changes that are suitable for rudimentary signaling or logic functions. This structural diversity reflects the quasiequivalence of flat-taper and conical self-assembling dendrons and the ability of flexible dendrimers to accommodate concomitant conformational and shape changes.

Thixotropic twin-dendritic organogelators.

Twin-dendritic organogelators have been prepared through selective functionalization of N-(3-aminopropyl)-1,3-propanediamine (APPDA) with self-assembling dendrons by using 1,1'-carbonyldiimidazole (CDI). Subsequent modification of the APPDA linker provided an additional degree of structural diversity by which to tailor the gelator self-assembly in bulk or in the gel state. These compounds are able to gel cyclohexane, toluene, n-butyl acetate, ethyl acetate, dichloromethane, and tetrahydrofuran. 3,4-Disubstituted apical branching units provided the most efficient organogelators and show a propensity to form thixotropic gels, wherein the gel recovers its elasticity after being subjected to shear. Structural and retrostructural analysis of the twin-dendritic organogelators reveals the bulk structural characteristics to be indicative of the subsequent gel properties. Diverse self-organized arrays were identified in bulk and all are able to form gels, thus indicating the role of quasiequivalence in mediating self-assembly in the gel state. Furthermore, we have found that porous columnar mesophases provide a strategy by which to prepare thixotropic gels. We demonstrate the importance of weak lateral hydrogen bonding within a column stratum versus hydrogen bonding along the length of the column for forming porous columnar mesophases and, by extension, thixotropic gels.

Self-assembling phenylpropyl ether dendronized helical polyphenylacetylenes.

The first example of a self-assembling phenylpropyl ether based dendronized polymer has been reported and its preferred helical handedness has been determined. Dendronized polymer poly(10) and its nondendritic analogue poly(8) are high-cis-content polyphenylacetylenes (PPAs) prepared by using [Rh(nbd)Cl]2/NEt3 (nbd: 2,5-norbornadiene). Both polymers possess a stereocenter in their side chain, which selects a preferred helical handedness. Based on negative exciton chirality observed in the CD spectra of poly(10), we have designated this molecule as a right-handed helical polymer, which persists over a wide temperature range. Poly(10) self-organizes into both Phiioh and Phih lattices in bulk. The Phiioh-to-Phih transition is associated with thermoreversible cis-cisoidal to cis-transoidal isomerization of the helical PPA, accompanied by a dramatic decrease in the column diameter and a decrease in the pi-stacking correlation length along the column. A model for the right-handed helical dendronized PPA has been proposed wherein dendrons from adjacent column strata interdigitate to effectively fill space.

Steric communication of chiral information observed in dendronized polyacetylenes.

Structural and retrostructural analysis of helical dendronized polyacetylenes (i.e., self-organizable polyacetylenes containing first generation dendrons or minidendrons as side groups) synthesized by the polymerization of minidendritic acetylenes with [Rh(nbd)Cl]2 (nbd = 2,5-norbornadiene) reveals an approximately 10% change in the average column stratum thickness (l) of the cylindrical macromolecules with a chiral periphery, through which a strong preference for a single-handed screw-sense is communicated. The cylindrical macromolecules reversibly interconvert between a three-dimensional (3D) centered rectangular lattice (Phi r-c,k) exhibiting long-range intracolumnar helical order at lower temperatures and a two-dimensional (2D) hexagonal columnar lattice (Phi h) with short-range helical order at higher temperatures. A polymer containing chiral, nonracemic peripheral alkyl tails is found to have a larger l as compared to the achiral polymers. In methyl cyclohexane solution, the same polymer exhibits an intense signal in circular dichroism (CD) spectra, whose intensity decreases upon heating. The observed change in l indicates that the chiral tails alter the polymer conformation from that of the corresponding polymer with achiral side chains. This change in conformation results in a relatively large free energy difference (DeltaGh) favoring one helix-sense over the other (per monomer residue). The capacity to distort the polymer conformation and corresponding free energy is related to the population of branches in the chiral tails and their distance from the polymer backbone by comparison to recently reported first and second generation dendronized polyphenylacetylenes.

Synthesis, structural analysis, and visualization of a library of dendronized polyphenylacetylenes.

A library of eleven high cis-content cis-transoidal polyphenylacetylenes (PPAs) dendronized with self-assembling dendrons was prepared from a library of fifteen convergently synthesized macromonomers. Using [Rh(C triple bond CPh)(nbd)(PPh(3))(2)] (nbd=2,5-norbornadiene) in the presence of 10 equiv of N,N-dimethylaminopyridine, predictive control over molecular weight and narrow molecular weight distribution are obtained. The PPA backbone serves as a helical scaffold for the self-assembling dendrons. The dendron primary structure dictates the diameter of the cylindrical PPAs in bulk, both in the self-organized hexagonal columnar (Phi(h)) lattice determined by X-ray diffraction (XRD) and in monolayers on highly ordered pyrolytic graphite (HOPG) and mica visualized by atomic force microscopy (AFM). Thermal and bulk phase characteristics of the cylindrical PPAs reinforces the generality that flexible polymer backbones adopt a helical conformation within the cylindrical macromolecules generated by polymers jacketed with self-assembling dendrons.

Thermoreversible cis-cisoidal to cis-transoidal isomerization of helical dendronized polyphenylacetylenes.

High cis content (81-99%) cis-transoidal polyphenylacetylene (PPA) jacketed with amphiphilic self-assembling dendrons, poly[(3,4-3,5)mG2-4EBn] with m = 8, 10, 12, 14, 16, and (S)-3,7-dimethyloctyl, were synthesized by Rh(C triple bond CPh)(nbd)(PPh(3))(2) (nbd = 2,5-norbornadiene)/N,N-(dimethylamino)pyridine (DMAP) catalyzed polymerization of macromonomers. The resulting cylindrical PPAs self-organize into hexagonal columnar lattices with intracolumnar order (Phi(h)(io)) and without (Phi(h)). The polymers with m = 12, 14, and 16 exhibit also a hexagonal columnar crystal phase (Phi(h,k)). The reversible Phi(h,k)-to-Phi(h)(io)-to- Phi(h) phase transition in these dendronized PPAs was analyzed by a combination of differential scanning calorimetry and small and wide-angle X-ray diffraction experiments performed on powder and oriented fibers. In the Phi(h,k) and Phi(h)(io) phases, the dendronized PPAs form helical porous columns. The helical pore disappears in the Phi(h) phase. This change is accompanied by a decrease of the external column diameter that is induced by stretching of the polymer backbone along the axis of the cylinder. The helix sense of the porous PPA is selected by homochiral alkyl dendritic tails. This transition is generated by an unprecedented conversion of the PPA backbone from the cis-cisoidal conformation in the Phi(h,k) and Phi(h)(io) phases to the cis-transoidal conformation in the Phi(h) phase. Under the same conditions, the pristine cis-PPA undergoes cis-trans isomerization and irreversible intramolecular 6pi electrocyclization of 1,3-cis,5-hexatriene sequences followed by chain cleavage. These processes are eliminated in the dendronized cis-PPA below its decomposition temperature.