Our research explores the interface between supramolecular chemistry, biology, catalysis and material science by studying dynamic combinatorial libraries: molecular networks involving dynamically exchanging chemical species. We study complex mixtures of interacting and interconverting molecules with particular focus on the new properties that can emerge from molecules acting collectively. We work in the emerging field of “Systems chemistry”. Our work is relevant to disparate fields ranging from the origins of life (self-replicating systems, dynamic kinetic stability) to materials chemistry (self-synthesising fibres, gels and surface functionalized nanoparticles). Several projects are currently underway.
Systems chemistry
Traditionally chemists have been trained to work with molecules in isolation, i.e., pure compounds. Yet biological systems function by virtue of an overwhelming complexity of interlinked molecular processes. Using modern analytical techniques we have started the study of complex mixtures of synthetic molecules that can interconvert as well as interact noncovalently. Such mixtures constitute networks that can transmit molecular information. New properties can be expected to emerge from molecules acting in concert that are relevant to understanding how Nature evolved its complex molecular networks and, ultimately, to the origins of life. Furthermore, once we have learned how to design and control complex molecular systems, we should be able to design new functions complementary to those encountered in Nature, and eventually we should be able to synthesize life de-novo.
From self-replication towards de-novo life
In 2010, we reported in Science the spontaneous emergence of two different self-replicating peptide-derived macrocycles from a complex equilibrium mixture. Both replicators compete for an identical feedstock. Competition is influenced by the mode of agitation: shaking favours one replicator while stirring leads to dominance of the other one. The process of self-replication is driven by self-organisation of the replicators into nanofibres large enough to be observed by electron microscopy and real-time AFM.
We have since extended this principle to other types of building blocks and have observed exciting phenomena, including adaptation to changes in the environment, emergence of parasites, molecular-recognition triggered replication, stochastic effects and behaviour that resembles speciation as it occurs in biology.
We currently focus on extending these systems in an effort to make life de-novo. This involves the integration of metabolism, compartmentalization and operating the systems far from equilibrium allowing them to undergo Darwinian evolution. A plausible path to a completely synthetic form of life is starting to be unveiled!
Self-Synthesizing Materials
Notwithstanding the development of many synthetic replicating systems, studies of the primitive evolution has been hampered by the inherently limited variability of the replicators. Supramolecular systems such as this one, being able to perform templated synthesis of themselves without any need of enzymatic machinery, enable us to study origins of life pathways.
The self-templated dynamic combinatorial libraries described above also constitute a promising method for the development of new self-assembling materials. Self-assembly provides the driving force to pull the system away from equilibrium, in favor of the very molecules that self-assemble, so that these materials can in effect be deemed self-synthesizing.
As the fibres described above form through a nucleation-growth mechanism, it is possible to control fibre length and achieve length distributions with uniquely narrow polydispersities. These results are among the first examples of living supramolecular polymerization and allow for the first time, access to supramolecular block-co-polymers.
We found that the self-assembled fibers produced by dynamic combinatorial chemistry can be further stabilized by rearranging the dynamic covalent disulfide bonds that were underlying the dynamic combinatorial process. We showed how photo-initiated disulfide exchange converts fibrous stacks of macrocycles into polymeric products, enhancing the stability of the fibers and causing gelation of the aqueous solution.
Self-synthesizing foldamer
Folding can bestow macromolecules with various properties, as evident from nature’s proteins. Until now complex folded molecules are either the product of evolution or of an elaborate process of design and synthesis. We recently discovered that molecules, that fold in a well-defined architecture of remarkable complexity, can emerge autonomously and selectively from a simple precursor. Specifically, we have identified a self-synthesizing macrocyclic foldamer with a complex and unprecedented secondary and tertiary structure, that constructs itself highly selectively from 15 identical peptide-nucleobase subunits, using a dynamic combinatorial chemistry approach. Folding of the structure drives its synthesis in 95% yield from a mixture of interconverting molecules of different ring sizes in a one-step process. Single crystal X-ray crystallography and NMR reveals a folding pattern based on an intricate network of noncovalent interactions involving residues space apart widely in the linear sequence. These results establish dynamic combinatorial chemistry as a powerful approach to developing synthetic molecules with folding motifs of a complexity that goes well beyond that accessible with current design approaches. The fact that such molecules can form autonomously implies that they may have played a role in the origin of life at earlier stages than previously thought possible.
Click on these images to view an animation of the foldamer crystal structure:
Receptors for biologically relevant targets from dynamic combinatorial libraries
We have developed reversible disulfide chemistry to produce dynamic combinatorial libraries of macrocyclic receptors arising from a mixture of many possible subunits. Adding a guest to a dynamic library results in a shift of the equilibrium in favour of the best host, which can then be identified and isolated. Using this approach we have developed receptors for a wide range of guests. For example, we discovered a receptor with nanomolar affinity for spermine (H2N-(CH2)3-NH-(CH2)4-NH-(CH2)3-NH2) which can indirectly control the conformation of DNA. The building block from which the receptor is made and the structure of the host-spermine complex are shown below.
The concept of dynamic combinatorial molecular recognition has also been applied in the field of anion receptors. Nanomolar affinity and impressive selectivity result from a delicate balance between rigidity and flexibility that is achieved only thanks to the diversity that a dynamic combinatorial library can produce, out of which the best receptor can emerge, which structure would otherwise be difficult to predict.
Dynamic Combinatorial Nanoparticles for Biomacromolecule Recognition
Combining the merits of dynamic combinatorial chemistry (DCC) as a tool for molecular recognition and nanoparticle systems renders a new approach to biomacromolecule detection by offering a platform with extended recognition surface and multivalent recognition. We aim to achieve highly specific surface functionalisation of hybrid nanoparticles through DCC. Nanoparticles decorated with functional groups that can participate in controllable reversible covalent bond formation have been prepared. Ligands as potential recognition units for biomacromolecules are then immobilized on the surface of nanoparticles through DCC. The recognition process is realized by exposing the equilibrium mixtures to the targets, which should lead to a shift in the product distribution towards the nanoparticles that have the highest affinity for the target molecules. We recently obtained the first very promising results using DNA as a template.
Towards Feedback Control over Catalysis in Dynamic Molecular Networks
This research area combines dynamic combinatorial chemistry in water with catalysis. The first step is to produce catalysts out of hydrazone or disulfide dynamic combinatorial libraries. In order for that to happen, the substrate should initially interact with the library so that a low-energy transition-state complex can be formed. If the product of the catalysis also interacts with the library members, feedback loops may emerge in the catalytic system. Our aim is to study these feedback loops and how they affect the rate of catalysis. We recently reported a dynamic molecular network in which the introduction of a substrate induced the transient formation of a catalyst that converts this substrate. After the substrate has been consumed the catalyst disappears by re-equilibrating into other library members.Selected publications:
- B. Liu, C. G. Pappas, E. Zangrando, N. Demitri, P. J. Chmielewski, S. Otto
Complex Molecules that Fold like Proteins Can Emerge Spontaneously
J. Am. Chem. Soc. 2019, 141, 4, 1685-1689. doi:10.1021/jacs.8b11698. - M. Altay, Y. Altay, S. Otto
Parasitic Behavior of Self‐Replicating Molecules
Angew. Chem. Int. Ed. 2018, 139, 10564–10568. doi:10.1002/anie.201804706. - I. Cvrtila, H. Fanlo-Virgós, Gaël Schaeffer, G. M. Santiago, S. Otto
Redox Control over Acyl Hydrazone Photoswitches
J. Am. Chem. Soc. 2017, 139, 12459-12465. doi:10.1021/jacs.7b03724. - B. M. Matysiak, P. Nowak, I. Cvrtila, C. G. Pappas, B. Liu, D. Komáromy, S. Otto
Antiparallel Dynamic Covalent Chemistries
J. Am. Chem. Soc. 2017, 139, 6744-6751. doi:10.1021/jacs.7b02575. - G. Ashkenasy, T. M. Hermans, S. Otto, A. F. Taylor
Systems chemistry
Chem. Soc. Rev. 2017, 46, 2543-2554. doi:10.1039/C7CS00117G. - J. W. Sadownik, E. Mattia, P. Nowak, S. Otto.
Diversification of self-replicating molecules.
Nature Chem. 2016, 8, 264-269. doi:10.1038/nchem.2419. - M. Colomb-Delsuc, E. Mattia, J. W. Sadownik, S. Otto.
Exponential self-replication enabled through a fibre elongation/breakage mechanism.
Nat. Commun. 2015, 6, 7427. doi:10.1038/ncomms8427. - J. M. A. Carnall, C. A. Waudby, A. M. Belenguer, M. C. A. Stuart, J. J.-P. Peyralans, S. Otto
Mechanosensitive self-replication driven by self-organization.
Science 2010, 327, 1502-1506. doi: 10.1126/science.1182767. - R. F. Ludlow, S. Otto
Systems chemistry.
Chem. Soc. Rev. 2008, 37, 101-108. doi: 10.1039/B611921M. - S. Otto, R. L. E. Furlan, J. K. M. Sanders
Selection and amplification of hosts from dynamic combinatorial libraries of macrocyclic disulfides.
Science 2002, 297, 590-593. doi: 10.1126/science.1072361.