Biophysics Colloquium by Joey Davis (Massachusetts Institute of Technology)

Joey Davis 
Assistant Professor of Biology, Massachusetts Institute of Technology

Interrogating highly heterogeneous structural ensembles in vitro and in cells: challenges and opportunities

Macromolecular machines such as the ribosome undergo massive structural changes as they assemble and function. While we have long appreciated such structural changes exist, experimentally visualizing and analyzing large ensembles of these structures is challenging. Here, I briefly describe cryoDRGN, a software package we developed to analyze structural heterogeneity in protein complexes visualized by cryo-electron microscopy (cryo-EM). This approach, which uses a purpose-built neural network based on a variational autoencoder, maps individual particle images to a low-dimensional latent space. Direct inspection of this latent space provides insights into the degree of structural heterogeneity in the dataset. Moreover, users can generate ensembles of three-dimensional structures from this latent space using the trained networks. In this seminar, I will describe our application of cryoDRGN to understand how a bacterial methyltransferase guides assembly of the small ribosomal subunit. In analyzing a series of related cryo-EM datasets, we surprisingly uncovered that this methyltransferase ‘proof-reads’ the assembling ribosomes by preferentially disassembling ribosomes that have been erroneously constructed. This unexpected insight into the bacterial ribosome biogenesis process was enabled by cryoDRGN, and it highlights the utility of our approach. I will additionally describe our work to newly develop analogous methods aimed at analyzing structural heterogeneity in situ via cryo-electron tomography.

Speaker Biography: Joseph (Joey) Davis is currently Assistant Professor of Biology at Massachusetts Institute of Technology. Joey Davis investigates how cells maintain a delicate internal balance of assembling and dismantling their own machinery — in particular, assemblages of many molecules known as macromolecular complexes.

Hosted by: Nozomi Ando

~ Coffee and tea provided ~