Abstract

Synthetic chemistry and synthetic biology offer complementary tools for manipulating the 3D architecture and function of biomacromolecules. In this seminar, I will outline two different projects that exemplify our hybrid approach to controlling peptide and protein architectures, making fundamental discoveries that have diverse potential applications from catalysis to cancer therapy. The first project involves the study of encapsulins, self-assembling protein cages that act as organelles in bacteria. There is substantial interest in using encapsulins as nanoreactors for hosting custom catalytic reactions, but remarkably little is known about their basic molecular properties, such as the fundamental dynamics of how substrates and products diffuse into and out of these cages. Using a combination of single particle cryo-EM, molecular dynamics, and stopped flow kinetics to study a library of designed cage variants, we uncover the complex interplay of factors that determines how these cages act as selectivity filters in their roles as organelles and catalytic nanoreactors. The second project involves the control of peptide conformation, using chemical cyclisation to develop inhibitory probes for studying protein targets implicated in cancer. We have developed cyclic peptides that can target cancers that are ‘ALT-positive’ – a term that accounts for 10-15% of all cancers, describing cells that use a non-canonical telomere extension pathway to achieve immortality. I will outline the discovery of peptide inhibitors with nanomolar affinity that disrupt FANCM -BTR, a key protein-protein interaction that regulates the proliferation of ALT -positive cancers, along with promising results from cellular assays on selected hits.