NINT Supramolecular Nanoscale Assembly Group Overview of Research

Unidimensional nanotubular objects have captivated the minds of the scientific community over the past decade because of their boundless potential in nanoscale science and technology. The strategies developed to achieve their synthesis spanned the areas of inorganic and organic chemistry and resulted in, for instance, carbon nanotubes, peptide nanotubes, as well as surfactant-derived tubular architectures. While inorganic systems benefit from the vast majority of the elements of the periodic table and the rich physical and chemical properties associated with them, organic systems inherited the power of synthetic molecular and supramolecular chemistry. As such, the latter approach offers limitless possibilities in terms of structural, physical and chemical engineering.

To establish the central role of supramolecular synthesis in nanoscale science and technology, we have recently introduced a new class of adaptive nanotubular architectures resulting from the self-assembly and self-organization of biologically inspired materials. The heterobicyclic base G ÙC, designed and prepared in our laboratories, features both the Watson-Crick H-bond donor-donor-acceptor of guanine and acceptor-acceptor-donor of cytosine on opposite faces of the molecule and a functional element on its non-hydrogen bonding face. (Fig. 1) Because of the asymmetry of its hydrogen bonding arrays, their spatial arrangement, and the hydrophobic character of the bicyclic system, G ÙC undergoes a hierarchical self-assembly process fueled by hydrophobic effects in water to form a six-membered supermacrocycle maintained by 18 H-bonds (Fig. 1). The resulting and substantially more hydrophobic aggregate self-organizes into a linear stack defining an open central channel running the length of the assembly (Fig. 1), the Rosette Nanotubes (RN). The inner diameter of the RN is directly related to the distance separating the hydrogen bonding arrays within the G ÙC motif while the peripheral diameter and its chemistry are dictated by the choice of the functional groups appended to this motif.

In principle, upon self-assembly, any functional group covalently attached to the G ÙC motif could be expressed on the surface of the nanotubes, thereby offering a general “built-in” strategy for tailoring the physical and chemical properties of the RN. We have synthesized over 70 G ÙC derivatives and we are currently investigating their aggregation properties. We have also developed a strategy whereby the nanotubes’ properties can be altered after self-assembly. In this “dial-in” approach, the G ÙC motif was designed so that the resulting nanotubes would express evenly distributed anchor points on their outer surface for further modification with external molecules (termed promoters here). This strategy offers a powerful approach to literally “dial-in” the desired properties by simply selecting promoters featuring the desired property such as charge, liquid crystallinity, hydrophobicity/hydrophilicity, fluorescence, transport (electrons, photons, ions). Finally, the third strategy, under development in our laboratories, consists in subjecting a set of G ÙC derivatives with predefined properties to an in-vitro evolution and selection scheme to generate adaptive RN featuring those properties.

The main objective of this work is to unveil the underlying and synergistic forces that fuel self-assembly processes, and to harness them for the design of supramolecular architectures with precisely defined properties, dimensions, topology, stereochemistry, hierarchy and shape. Central to these fundamental questions is the establishment of the structural and electronic factors (charge densities, ionization states, tautomeric equilibria) associated with the G ÙC base and their relationship to the formation of stable RN. As a result, the Supramolecular Nanoscale Assembly Group works on (a) the development of efficient synthetic strategies for the preparation of G ÙC analogs and derivatives, (b) the investigation of the structural, chemical and physical factors affecting their self-assembling properties, (c) the establishment of a relationship between tautomeric equilibria, pKa’s, charge density, dipole moments and stability of the RN using computational, synthetic and physical methods, and (d) the synthesis of 15N labeled G ÙC motifs to explore the dynamics and establish the structural integrity of the RN in solution under various experimental conditions (temperature, pH, ionic strength, solvents, additives).

This research program has contributed to a multidisciplinary environment within the Supramolecular Nanoscale Assembly Group and NINT. In addition to exploring new aspects of heterocyclic, nucleic acids and peptide chemistry, the students and postdoctorates involved in this project, learn how to synthetically engineer non-covalent interactions to generate higher order assemblies with predefined shape structure, and function (supramolecular synthesis). Subsequent physical organic studies to characterize the resulting assemblies entice them to learn state-of-the-art high field 2D 1H-NMR techniques, dynamic and static light scattering, circular dichroism, electron microscopy (TEM, SEM), XRD, SAXS, SANS, and scanning probe microscopy (AFM, STM). The graduate students benefit tremendously from their postdoctoral colleagues, while the undergraduate students learn the basic laboratory techniques from their graduate student partners and get to discover and appreciate what may become the next step in their academic careers.

 Spectrocopically Encoded Polymers. A second important area of interest to the Supramolecular Nanoscale Assembly Group is in the area of combinatorial chemistry. The essence of this field is the rational and informed selection of diversity elements followed by their combinatorial association within a predefined framework to generate a chemical library.

We have recently introduced on a new class of resins prepared with built-in infrared and Raman spectroscopic barcodes. This approach introduces a new paradigm in combinatorial chemistry, as the beads are no longer just carriers for solid phase synthesis, but are in addition the repository of the synthetic scheme to which they were subjected. In conjunction with a directed sorting strategy at the single bead level, automated target-oriented synthesis and diversity-oriented synthesis of libraries in which each compound is assigned a unique barcode at the outset of a split-pool synthesis is now achievable. Because the loading, size and the number of beads representing a given compound-barcode could be varied almost at will, the quantity of each synthetic intermediate and library member could, as a result, be tuned to carry out routine spectroscopic characterizations at any stage of the library synthesis and on-bead or solution phase biological evaluations.

Besides drug discovery, the barcoded resins offer numerous opportunities in catalyst discovery, biomedical diagnostics, dynamic combinatorial chemistry, genomics and proteomics (Fig. 2).