Oligonucleotide-based systems for input-controlled and non-covalently regulated protein binding

Abstract

Supramolecular chemists continuously take inspiration from complex biological systems to develop functional molecules involved in molecular recognition and self-assembly. In this regard, ‘smart’ synthetic molecules that emulate allosteric proteins are both exciting and challenging, because many allosteric proteins can be considered as molecular switches that bind to other protein targets in a non-covalent fashion and, importantly, are capable of having their output activity controlled by prior binding to input molecules. This review discusses the foundations and passage towards the development of non-covalently operated oligonucleotide-based systems with protein-binding capacity that can be precisely regulated in an input-controlled manner.

Keywords::

• input responsive
• protein binding
• oligonucleotide
• supramolecular
• structure switching
• multivalency

Acknowledgements

The authors gratefully acknowledge funding provided by the Louisiana Board of Regents RCS (LEQSF (2009-12)-RD-A-17) and the National Institutes of Health (R01GM097571). C.H.B. acknowledges the Louisiana Board of Regents for a graduate fellowship, and that this material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. (DGE-1154145).

Notes

^1. In addition to being inspired by biological systems, supramolecular chemists have also developed a range of synthetic systems that interface with biology. For further reading, please see the following references (123456789101112).

^2. Other functions include covalent modification (such as phosphorylation) of the downstream protein target.

^3. Nucleic acid-based enzymes is also an important area of research that is, however, outside the scope of this review. For recent overviews on the use of enzymatic RNA and DNA systems, please see references (272829).

^4. A range of supramolecular approaches have been used to bind to and control proteins, from synthetic peptides (2) to metal-mediated assemblies (30) and DNA-based molecular springs (31, 32). Several recent reviews highlight some of the approaches not discussed in detail here (7891012).

^5. While not a system working via multivalent protein binding, per se, the groups of Muruyama and Goto (96) have used a similar multi-stranded hybridisation method to organise Thrombin using sequentially hybridised TBAs.