Principal Supervisor: Dr. Sarah PikeLink opens in a new window

Co-supervisor: Dr. Anna Peacock

PhD project title: Metallo Foldamer-Proteins Hybrids: Novel Biomimetic Scaffolds for Sensing and Imaging Applications

University of Registration: University of Birmingham

Project outline:

Background: Foldamers are synthetic helical oligomers that adopt stable secondary structures through mimicking the folding patterns of biological systems to generate structures of well-defined size and shape (Figure 1).¹ Foldamers have been the subject of great interest due to their diverse range of applications in supramolecular chemistry. However, despite the importance of biomimetic foldamers and their known ability to mimic the simple natural helical topologies, there are no reports on the development of higher order foldamer scaffolds that can mimic the sophisticated tertiary and quaternary topological structures found in biological systems. Given that the shape of the foldamer scaffold controls their (photo)physical properties and, in turn their function, accessing new to higher order topologies has the exciting potential to open up the field towards optimising existing applications or generating new applications with these novel structures (e.g., as sensors for biological analytes or medical diagnostics).

Figure 1. Stable folded conformation of synthetic organic helical oligomer (foldamer) in the solid state. a) viewed side on, b) viewed from the N terminus.

 De novo designed metallopeptide scaffolds that adopt well-defined coiled-coil motifs (Figure 2) can be accessed through combining the fields of inorganic chemistry with synthetic biology (i.e. by incorporating metals into folded biological building blocks (peptides) to create new metallopeptide scaffolds).² In recent years, de novo metallopeptide coiled-coil scaffolds, have found impressive applications as MRI contrast agents.³ However, the fact that these existing metallopeptide coiled-coil scaffolds are made from biological building blocks, means that they are based on, and therefore limited, to biological shapes and structures. Accordingly, existing systems are restricted to exhibiting a range of shapes and structures, that historically have been limited by evolutionary-imposed constraints, and this severely hinders the optimisation of their performance and the accessibility of new scaffolds for innovative applications.

As it is necessary to tune and improve the photophysical properties of these scaffolds in order to optimise their performance for applications beyond biology, including as sensors and luminescent or magnetic probes for medical purposes, it is vital that we are able to access new topologies that are not restricted to biomimetic systems with evolution-imposed constraints. Accordingly, we will create new hybrid metallofoldamer-protein systems that adopt higher order coiled coil assemblies which are able to adopt a range of novel topologies for generating new applications as potential sensors for biological analytes or effective medical diagnostics tools.

Figure 2. a) Coiled-coil scaffold incorporating lanthanide ions, b) de novo coiled-coil lanthanide design for potential MRI imaging and luminescence purposes.

Objectives

1) To create a new class of coiled-coil systems based on hybrid metallofoldamer-protein scaffolds and fully characterize them using standard and advanced analytical and spectroscopic techniques.

2) To generate libraries of hybrid metallofoldamer-peptide scaffolds wherein fundamental structural features (e.g., type of metal) are systematically varied to provide a broad scope of substrates and a vast library of hybrid scaffolds.

3) To optimise the photophysical or magnetic properties of the new hybrid metallofoldamer-protein scaffolds and establish structure-activity and function relationships on the influence of key structural features (e.g., foldamer length, foldamer building block and/or type of metal) on their performance as sensors for biological analytes and as luminescent or magnetic probes for medical imaging applications.

Methodology: Each of the objectives of the project require a combination of organic chemistry synthesis and advanced analytical study to generate the new hybrid metallofoldamer-protein scaffolds and to assess their stability and performance as sensors and as luminescent or magnetic probes. This work will be carried out under the supervision of Drs. Pike and Peacock in the Department of Chemistry.


References:

[1] G. Guichard, I. Huc, Chem. Commun., 2011, 47, 5933-5941.

[2] H. R. Marsden, A. Kros, Angew. Chem. Int. Ed., 2010, 49, 2988-3005.

[3] A. F. A. Peacock et al., Dalton Trans., 2018, 47, 10784.

 

BBSRC Strategic Research Priority: Understanding the rules of life – Structural Biology, and Systems Biology

 

Techniques that will be undertaken during the project:

The candidate will develop a range of standard and advanced organic and biological chemistry synthetic skills. The candidate will also develop a wide-range of analytical skills and techniques over the course of the PhD including, UV/Vis, circular dichroism (CD) spectroscopy, mass spectrometry, infrared spectroscopy, and NMR spectroscopy (including ¹H and ¹³C NMR and 2D-correlation techniques) and single-crystal X-ray diffraction analysis. The candidate will develop a multi-disciplinary skillset with expertise in organic, biological and inorganic chemistry design, synthesis and characterisation (including crucially elucidating 3-dimensional structure), as well as cultivating important keys skills relating to science communication and developing the ability to tackle tasks through problem-based thinking and analysis. Upon completion of the PhD, the candidate will be equipped with the necessary skills to pursue a future career in academia or industry.

Contact: Dr. Sarah PikeLink opens in a new window