This post is prompted by a set of interrelated advances in chemistry that hold great promise for advancing the art of atomically precise fabrication. In this post, I’ll describe an emerging class of modular synthesis methods for making a diverse set of small, complex molecular building blocks.
The road to complex self-assembled nanosystems starts with stable molecular building blocks, and the more choices, the better. Self-assembly and the folding of foldamers are similar processes: They work when parts fit together well, and in just one way. Having building blocks to choose from at the design stage will typically make possible a better fit, resulting in a denser, more stable structure.
Building blocks for building blocks for building blocks
I often think in terms of four levels of molecular assembly:
- Specialized covalent chemistry to synthesize monomers
(~1 nm) - Modular covalent chemistry to link monomers to make oligomers
(~10 nm length) - Intramolecular self-assembly (folding) to make 3D objects
(< 10 nm diameter) - Intermolecular self-assembly to make functional systems
(~10–1000 nm)
Recent developments are blurring the first level into the second, however, because new modular chemistries can make complex structures that can serve a monomers at the next level of assembly. Perhaps the most outstanding example comes from Marty Burke’s lab, which has pioneered a new, combinatorial methodology for piecing together small molecules of enormous diversity. From the lab website:
To most effectively harness the potential impact of complex small molecules on both science and medicine, it is critical to maximize the simplicity, efficiency, and flexibility with which these types of compounds can be synthesized in the laboratory.
…the process of peptide synthesis is routinely automated. As a result, this highly enabling methodology is accessible to a broad range of scientists. In sharp contrast, the laboratory synthesis of small molecules remains a relatively complex and non-systematized process. We are currently developing a simple and highly modular strategy for making small molecules which is analogous to peptide synthesis…
Our long term goal is to create a general and automated process for the simple and flexible construction of a broad range of complex small molecules, thereby making this powerful discovery engine widely accessible, even to the non-chemist.
In outline, the Burke group’s method exploits iterative Suzuki-Miyaura coupling, a mild and increasingly general technique in which (in Burke’s approach) carbon-carbon bond formation plays the role of amide bond formation in making peptides. In peptide synthesis, suitably-protected amino acids are iteratively coupled, deprotecting the terminal amine at each step. In Burke’s method, suitably-protected boronic acids play the analogous role.
The key advance is the N-methyliminodiacetic acid (MIDA) protecting group, a trivalent ligand that rehybridizes the boron center from sp2 to sp3, thereby filling and blocking access to the open p orbital that makes trivalent boron compounds so wonderfully, gently reactive. The resulting complex is stable to a wide range of aggressive conditions, including powerful oxidants and strong acids. It can be removed, however, by an aqueous base (e.g., sodium bicarbonate in water).
For more information, good places to start are the Burke lab’s research overview page, and the MIDA boronate technology spotlight page at Sigma-Aldrich, which also provides off-the-shelf MIDA-protected building blocks. Sigma-Aldrich offers a larger universe of boronic acids and boronic esters, as does CombiPhos Catalysts. It’s worth looking through one of these documents to get a gut sense of what’s now available. Impressive diversity, compared to the 20 standard amino acid side chains.
(For a general perspective on this direction of development, see “Controlled Iterative Cross-Coupling: On the Way to the Automation of Organic Synthesis”, Angew. Chem. Int. Ed. 2009.)
More than a protecting group
The MIDA boronate ester is an example of a broader class of structures that are important in their own right. The demands of organic synthesis have brought forth a vast range of commercially available boronate esters (see links above), and this investment gives a free ride to scientists aiming to exploit them as building blocks. As linkers for self-assembled structures, boronate esters are both extraordinary and underexploited.
Relying a little less on hydrogen bonds, and a little more on bonds that can hold a self-assembled solid together at 600°C — dull red heat — could increase the robustness of self-assembled products. A fast, reversible, aqueous, biocompatible boron chemistry opens a door.
More later.
[Updated, 5 Feb: The boron chemistry in question opens “a door”, not “the door”]
See also:
- Modular Molecular Composite Nanosystems
- A High-Performance Polymer for Nanosytems Engineering
- CAD for Nanoengineering: DNA, proteins, and search-intensive design
{ 3 comments… read them below or add one }
I like to think that you could design foldamers such that they form self-assembling building blocks. You would, for example, design cubic shaped foldamers with very specific faces, and a “face-match catalyzed” covalent bonding mechanism that will irreversibly bond pairs of faces that match. You could then program the self-assembly of specific configurations of nearly unlimited numbers of such building blocks simply by generating them with the right combinations of faces.
One problem with this approach, obviously, is that such assemblies would be static, at least in this simple concept. It is much harder to imagine how you would self-assemble machinery that is capable of motion, i.e. has more than one valid spacial configuration.
It is not trivial to specify the face-combinations that would result in a unique configuration. This can be, and probably has been, explored computationally, today.
As a more general remark, I have a concern with molecular manufacturing that I have so far not seen addressed here or elsewhere. Because of the absence of people on the nano-scale, any manufacturing has to be completely automatic. Complete automation is not impossible, and today we are coming close to it in our manufacturing facilities. However, we are taking advantage of Feynman’s “room at the bottom” in our control circuitry. That control circuitry is many orders of magnitude smaller than the machine parts (approaching nanometers these days), allowing us to put, say, the controller for a CNC machine in a small box right next to the machine.
In nanosystems, there is no such room at the bottom. Is this a problem? How can it be addressed? Forgive me if this has been discussed before, I am fairly new to this subject.
So… basically this sounds like we’re at the stage where we can build lego bricks. In the range from Duplo to Technics, where would you put this?
The rate at which advances are being made is very encouraging.
@ Eniac — Thanks, you raise several important questions.
In fact, my reply grew into a post: “Self assembly and nanomachines: Complexity, motion, and computational control”.
{ 4 trackbacks }