Molecular Machines made from Lasso Peptides
Final Report Abstract
In summary, the main goal of the present project was to develop a synthesis strategy that allows the construction of functional, mechanically interlocked molecules, such as rotaxanes and catenanes, solely made from peptides without synthetic support structures in water. While entangled peptide and protein structures occur in nature, the chemical synthesis of these architectures is still associated with great difficulties today. Mechanically interlocked peptides (MIPs) can be used for generating controlled and directed motion at the molecular level and are therefore ideal prototypes for biocompatible molecular switches and machines. Functional MIPs are very promising structures for applications in the field of biopharmaceuticals and biomaterials with a high potential of commercial relevance in the near future. The project was structured into three major aims: (i) the development of a lasso peptide toolbox for MIP formation, (ii) assembly of MIPs and (iii) building motion into MIPs (i.e. finding ways to control large-amplitude molecular motion). Based on first experiments, we quickly realized that initially outlined synthesis strategy using modified lasso peptides is synthetically challenging, as chemical post-modification of lasso peptides turned out to be difficult. As a result, we redesigned the project and pursued a dynamic covalent synthesis strategy. For this, we used genetic engineering and protease reactions to create cysteine-decorated peptide [2]rotaxanes, which serve as supramolecular building blocks for dynamic covalent self-assembly. These building blocks accordingly form dynamic combinatorial libraries in aqueous solutions by air oxidation. The rational positioning of cysteine residues predetermines the structures of the resulting MIPs. We were able to create a set of different disulfide-bonded MIPs including [n]catenanes, [n]daisy chains, rotaxanes and double lasso macrocycles. Detailed analytical characterization of a peptide [2]catenane showed that MIPs can have complex structural dynamics on different time scales, which is particularly promising for the control of molecular motions. In a recently published article, we have studied such a large-amplitude motion of a peptide macrocycle (so-called molecular shuttling) in further detail. It turns out that mainly mechanical strain in MIPs and non-covalent interactions between subcomponents govern the (co-)conformational motion. The results of this project build an important basis for a general understanding of the synthesis of complex biomolecular structures and will help to find synthetic ways towards entangled peptides. In a next step, the development of new synthesis methods (e.g. novel template strategies) is needed that allow chemical synthesis of MIPs, especially stimuliresponsive MIPs with mobile subcomponents. The long-term goal, the total synthesis of functional MIPs, would open up a new field in nanotechnology and enable the commercialization of these highly interesting synthetic targets.
Publications
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Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide, Front. Bioeng. Biotech. 2020, 8, 1001–1018
W. K. Chou, M. Vaikunthan, H. V. Schröder, A. J. Link, H. Kim, M. P. Brynildsen
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Cellulonodin-2 and Lihuanodin: Lasso Peptides with an Aspartimide Post-translational Modification, J. Am. Chem. Soc. 2021, 143, 11690–11702
L. Cao, M. Beiser, J. D. Koos, M. Orlova, H. E. Elashal, H. V. Schröder, A. J. Link
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Dynamic Covalent Self-Assembly of Mechanically Interlocked Molecules Solely Made From Peptides, Nat. Chem. 2021, 13, 850–857
H. V. Schröder, Y. Zhang, A. J. Link
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The Shuttling Cascade in Lasso Peptide Benenodin-1 is Controlled by Non-Covalent Interactions, Chem. Eur. J 2021
H. V. Schröder, M. Stadlmeier, M. Wühr, A. J. Link
