Molecular Machines from Adapted Transcription Factor-DNA Complexes

Scientists are investing significant effort into developing small molecular machines capable of translational or rotational motion at the molecular level in response to an external stimulus, with potential future applications in molecular electronics and data storage.[1] In chemistry, these systems are often based on supramolecular architectures such as catenanes (two mechanically interlocked macrocycles) or rotaxanes (a threaded macrocycle with stoppers) which contain individual components held together by a topological bond. Chemical docking stations which utilise recognition motifs are required in order to control molecular motion. However, most docking stations are not that sophisticated nor selective and can be difficult to make. In contrast, biomolecular recognition in nature is extremely sophisticated, whilst being highly selective. This project therefore sets out to utilise DNA-peptide recognition, using protein and DNA segments as the building blocks, to generate novel molecular machines from biological components.

Proteins such as transcription factors (e.g. the bZIP family) can bind to DNA with a high degree of sequence selectivity.[2] Often direct contact is made between the DNA target site and a relatively short protein segment, commonly an alpha-helix, despite the original protein being much larger. A number of examples now exist which demonstrate that this small protein fragment alone can still display similar sequence-selective DNA binding, and therefore these fragments and DNA represent attractive building blocks for assembling molecular machine-type architectures.[3]

In this project the student will study shortened versions of the bZIP family of transcription factor proteins, prepared using automated peptide synthesis. He/she will then assess how their adaptation and cyclisation affects their binding to DNA sequences. Synthetic DNA containing two target sites with different affinities (e.g. double stranded DNA, dsDNA vs single stranded DNA, ssDNA) will also be prepared to assess how selective the adapted transcription factors are in their binding to DNA. This is turn will lead to the design of shuttling machines displaying molecular motion in which peptide motion along the DNA axis between docking stations can be controlled using enzymatic synthesis of dsDNA.

Funding notes:

This project is part of the BBSRC MIBTP programme, involving the University of Birmingham and other partner universities. Students are welcomed from diverse pathways and backgrounds. Our vibrant international student body thrives in an environment that values creativity and expertise across many scientific disciplines.

The studentship comes with a comprehensive support package, including fees, a tax-free annual stipend, a travel and conference budget, a consumables budget, and a MacBook Pro. International students are welcome to apply, with international fees covered by University of Birmingham funding.

To apply, use the following link for instructions. Then click on 'Chemistry' and find the project title: https://www.birmingham.ac.uk/research/activity/mibtp

References:

[1] https://www.nobelprize.org/uploads/2018/06/popular-chemistryprize2016-1.pdf

[2] M. A. Schumacher et al., The Structure of a CREB bZIPzSomatostatin CRE Complex Reveals the Basis for Selective Dimerization and Divalent Cation-enhanced DNA Binding, J. Biol. Chem., 2000, 275, 35242–35247, https://doi.org/10.1074/jbc.M007293200

[3] G. A. Bullen, et al., Exploiting anthracene photodimerization within peptides: light induced sequence-selective DNA binding. Chem. Comm., 2015, 51, 8130-8133, https://doi.org/10.1039/C5CC01618E