Math-Bio: Modeling reveals the strength of weak interactions in stacked ring assembly

It’s my great pleasure to announce the continuation of our weekly Math-Bio seminar series! As a reminder, these meetings take place every Wednesday at 2:00 pm (Pacific Time) in the PIMS lounge (ESB 4133). PIMS tea will follow the seminar at around 3:00 pm.

Cells employ large macromolecular machines for the execution and regulation of many vital processes for cell and  organismal viability. Interestingly, cells cannot synthesize these machines as functioning units. Instead, cells synthesize the molecular parts that must then assemble into the functional complex. An extremely common motif is a stacked ring-like topology. Thus, understanding how stacked trimers assemble is crucial for our understanding of how complexes are regulated. Here, we developed a mathematical model of stacked trimer assembly that accounts for different binding affinities between and within rings. Our main finding is that deadlock – a severe form of kinetic trapping– can be extremely long, lasting for days or longer. Deadlock is worst when all the interfaces have high binding affinities. So, we predict that evolutionary pressures select against stacked trimers having strong binding affinities throughout. We tested our prediction by analyzing solved stacked trimer structures; we found that indeed the majority – if not all – of the stacked trimers did not contain very strong interactions. Finally, to better understand the origins of deadlock, our pathway analysis show that when all the binding affinities are strong, many of the possible pathways are utilized, consuming subunits, and creating high levels of deadlock. In sum, our work provides critical insight into the evolutionary pressures that have shaped the assembly of stacked rings.