Biomimetic nanotechnology with synthetic macromolecules

This is a draft of a piece I’ve been invited to write for the special edition of Journal of Polymer Science: Polymer Physics Edition that is associated with the March meeting of the American Physical Society. The editors invited views from a few people about where they saw the future of polymer science. Here’s my contribution, with themes that will be familiar to readers of Soft Machines. Since the intended audience consists of active researchers in polymer science, the piece has more unexplained technical language than I usually use here.

In the first half of the twentieth century, polymer science and biochemistry developed together. With synthetic polymer chemistry in its infancy, most laboratory examples of macromolecules were of natural origin, and the conceptual foundations of polymer science, such as Staudinger’s macromolecular hypothesis, were as important for biology as for chemistry. Techniques for the physical characterisation of macromolecules, like Svedberg’s ultracentrifuge, were applied as much to biological macromolecules as synthetic ones. But with the tremendous development of the field of structural biology that x-ray protein crystallography made possible, the preoccupations of polymer science increasingly diverged from those of what was now being termed molecular biology. The issues that are so central to protein structure – secondary and tertiary structural motifs, ligand-receptor interactions and allostery, had no real analogue in synthetic polymer science. Meanwhile, the issues that exercised polymer scientists – crystallisation, melt dynamics and rheology – had little relevance to biology. Of course there were exceptions, but conceptually and culturally the two disciplines had become worlds apart.

I believe that the next fifty years we need to see much more interaction between polymer science and cell biology. In polymer science, we’ve seen the focus shift away from the properties of bulk materials to the search for new functionality by design at the molecular level. In cell biology, the new methods of single molecule biophysics permit us to study the behaviour of biological macromolecules in their natural habitat, rather than in a protein crystal, allowing us to see how these molecular machines actually work. Meanwhile synthetic polymer chemistry has started to give us access to control over molecular architecture. This is not yet at the precision that we obtain from biology, but we are already seeing the exploitation of non-trivial macromolecular architectures to achieve control over structure and function. The next stage is surely to take the insights from single molecule biophysics about how biological molecular machines work and design synthetic molecules to perform similar tasks.

We could call this field biomimetic nanotechnology. Biomimetics, of course, is a well-known field in material science; what we are talking about here is biomimetics at the level of single molecules, at the level of cell biology. Can we make synthetic analogues of molecular motors and other energy conversion devices? Can we learn from membrane biophysics to make selective pumps and valves, which would allow the easy and energy-efficient separation and sorting of molecules? Will it be possible to create any synthetic analogue of the systems of molecular sensing, communication and computation that systems biology is just starting to unravel? It’s surely only by achieving this degree of nanoscale control that the promise of molecular medicine could be fulfilled, to give just one example of a potential application.

What are the areas of polymer science that need to be advanced to enable these developments? Obviously, in polymer chemistry, synthesis with precise architectural control is key, and achieving this goal in water-soluble systems is going to be important if this technology is going to find wide use, particularly in medical applications. Polymer physicists are still much less comfortable dealing with systems involving water and charges than with polymer solutions in simple non-polar solvents, and we’ll need more work to ensure that we have a good understanding of the physical environment in which our devices will be operating.

The importance of self-assembly as a central theme will continue to grow. This way of creating intricate nanostructures by programmed interactions in macromolecules is well known to polymer science; the richness of the morphologies that can be obtained in block copolymer systems is well-known. But in comparison with the sophistication of biological self-assembly, synthetic self-assembly still operates at a very crude level. One new element that we should import from biology is the exploitation of secondary structure and its coupling to nanoscale morphology. Another important idea is to exploit the single chain folding of a sequenced copolymer in an analogue of protein folding. This, of course, would require considerable precision in synthesis, but theoretical developments are also necessary. We have learnt from the theory of protein folding theory that only a small fraction of possible sequences are foldable, so we will need to learn how to design foldable sequences.

Another important principle will be exploiting molecular shape change. In biology, this principle underlies the operation of most sophisticated nanoscale machines, including molecular motors, ion channel proteins and signalling molecules. In polymer physics the phenomenon of the coil-globule transition in response to changing solvent conditions is well known and has its macroscopic counterpart in thermoresponsive gels. To be widely useful, we need to engineer responsive systems with much more specific triggers and with a more highly amplified response. One promising way of doing this uses the coupling between transitions in secondary structure and global conformation; however we’re still a long way from the remarkable lever arms of biological motor proteins, in which rather subtle changes at a binding site produce a large overall mechanical response.

Some of the most powerful ideas from biology still remain essentially unexploited. An obvious one is, of course, evolution. At the molecular level, evolution offers a spectacularly powerful way of searching multidimensional parameter spaces to find efficient design solutions. It’s arguable that, given the combinatorial complexity that arises with even modest degrees of architectural control and our unfamiliarity with the design rules that are appropriate for the nanoscale environment, that significant progress will positively require some kind of evolutionary approach, whether that is executed in computer simulation or with real molecules.

Perhaps the most fundamental difference between the operating environments of biology and polymer science is the question of thermodynamic equilibrium. Polymer scientists are used to systems at, or perturbed slightly away from, equilibrium, while biological systems are driven far from equilibrium by a continuous energy input. How can we incorporate this most basic feature of life into our synthetic devices? What will be our synthetic analogue of life’s universal energy currency, adenosine triphosphate?

Ultimately, what we are talking about here is the reverse engineering of biology. It’s obvious that the gulf between the crudities of synthetic polymer science and the intricacies of cell biology is currently immense (certainly quite big enough to mean that the undoubted ethical issues that would arise if we could make any kind of reasonable facsimile of life are still very distant). Nonetheless, even rudimentary devices inspired by cell biology would be of huge practical benefit. Potentially even more significant a benefit than this, though, would be the deep understanding of the workings of biology that would arise from trying to copy it.