The Big Picture

I'm using coarse-grained molecular dynamics simulations to inform how to engineer substrate specificity into enzymes.

Proteins are large, dynamic molecules. Enzymes, especially, often undergo large conformational changes as they carry out their function. These motions and complexity make it difficult to rationally engineer desired functions into these molecules. An integrative structural approach can help us understand which parts of the enzyme are most important to its function, but it is slow and expensive to iteratively prototype variants of interest. Molecular dynamics simulations can help: we can simulation known, functionally-important motions, and then systematically observe how mutations in silico affect those motions. 

I'm applying this approach to engineer substrate-specific cryptidase enzymes. Cryptidases are a class of enzyme with a hollow core in which they capture, unfold, and degrade various biologically-significant peptide substrates, including insulin, amyloid beta, and big endothelin. These substrates have made cryptidases an exciting target for clinical intervention, but their substrate promiscuity has made it difficult to convert on this promise. It is my hope that robust simulations of enzyme activity against their diverse substrates will reveal key interactions that can be varied to create single-substrate-selective versions of these enzymes, which could eventually be applied clinically to help patients with Alzheimer's disease, diabetes, and more.