Programming the Supramolecular Helical Polymerization of Dendritic Dipeptides via the Stereochemical Information of the Dipeptide

Abstract

Many natural biomacromolecules are homochiral and are built from constituents possessing identical handedness. The construction of synthetic molecules, macromolecules, and supramolecular structures with tailored stereochemical sequences can detail the relationship between chirality and function and provide insight into the process that leads to the selection of handedness and amplification of chirality. Dendritic dipeptides, previously reported from our laboratory, self-assemble into helical porous columns and serve as fundamental mimics of natural porous helix-forming proteins and supramolecular polymers. Herein, the synthesis of all stereochemical permutations of a self-assembling dendritic dipeptide including homochiral, heterochiral, and differentially racemized variants is reported. A combination of CD/UV-vis spectroscopy in solution and in film, X-ray diffraction, and differential scanning calorimetry studies in solid state established the role of the stereochemistry of the dipeptide on the thermodynamics and mechanism of self-assembly. It was found that the highest degree of stereochemical purity, enantiopure homochiral dendritic dipeptides, exhibits the most thermodynamically favorable self-assembly process in solution corresponding to the greatest degree of helical order and intracolumnar crystallization in solid state. Reducing the stereochemical purity of the dendritic dipeptide through heterochirality or by partially or fully racemizing the dendritic dipeptide destructively interferes with the self-assembly process. All dendritic dipeptides were shown to coassemble into single columns regardless of their stereochemistry. Because these columns exhibit no deracemization, the thermodynamic advantage of enantiopurity and homochirality suggests a mechanism for stereochemical selection and chiral amplification.

Self-Assembly of Dendritic Dipeptides as a Model of Chiral Selection in Primitive Biological Systems

“…5. No net ellipticity was observed by CD analysis of the DL-DL dendron in solution, yet the UV-vis data supported the cooperative formation of a supramolecular column and allowed one to distinguish between three different self-assembly pathways [67]. As illustrated in Fig.…”

“…A concise strategy was derived for the preparation of chiral dendritic dipeptides. A dipeptide Tyr-Ala was synthesized with tertbutoxycarbonyl (Boc) protection of the N-terminus and methyl ester protection of the C-terminus (Boc-Tyr-Ala-OMe [66,67]. Helical diffraction theory applied to the oriented fiber X-ray diffraction pattern provides information on the spatial disposition of the dendritic dipeptides in the columns [64].…”

“…As discussed more extensively in the preceding section, the stereochemistry of Tyr governs the helix handedness, while the stereochemistry of Ala determines the structural features of the columns. The homochiral supramolecular dendrimers were found to be more enthalpically favorable and to form slightly smaller pores than the heterochiral dendritic dipeptides [67].…”

“…As mentioned above (Fig. 5), the four partially racemized dendritic dipeptides L-DL, D-DL, DL-L, and DL-D, containing one chiral amino acid and one racemic amino acid, were prepared [67]. Each of these racemized structures is an equimolar mixture of diastereomeric homochiral and Two different self-assembly pathways can be anticipated for the partially racemized dendrons.…”

Supramolecular chirality in self-assembled peptide amphiphile nanostructures

“…Molecular chirality of peptides can be used to induce supramolecular chirality upon assembly of individual molecules into one-dimensional nanostructures. [12][13][14] Effective assembly of this type can be achieved when a certain peptide sequence is attached to a hydrophobic fatty acid. Aliphatic peptide amphiphiles (PAs) possess this type of design and exhibit self-assembly properties.…”