The de novo design of lanthanide coiled coils for imaging applications

Berwick, Matthew Robert (2016). The de novo design of lanthanide coiled coils for imaging applications. University of Birmingham. Ph.D.

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Abstract

This thesis describes the design, synthesis and evaluation of a series of \(de\) \(novo\) designed peptide sequences for lanthanide binding, with the aim of creating a new class of imaging agents for luminescence and magnetic resonance imaging, due to the potential of controlling the complexes water coordination and rotational correlation time. The peptides were designed to form trimeric coiled coil motifs, with a lanthanide binding site incorporated inside the hydrophobic core. This binding site was generated using solely naturally occurring amino acids and was found to be specific for lanthanides over other biologically relevant metals. A 10 Å translation of the binding site, throughout the peptide sequence, was shown to influence the coiled coil stability and metal coordination, with the amino acids in the central binding sites saturating the lanthanide coordination. Whereas, when the binding site was located at the extremities of the peptide sequence, not all of the donor ligands were required, resulting in the presence of up to three exogenous water molecules. Ultimately, this had profound effects on the relaxivity of the complexes, with a four-fold variation in the transverse relaxivity observed, but importantly all designed peptides displayed an increase in relaxivity compared to current MRI contrast agents.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):