Abstract 1392 Modeling reveals the strength of weak interactions in stacked ring assembly

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 rings assemble is crucial for our understanding of how macromolecular complexes are regulated.In this work, we developed a mathematical deterministic model of stacked trimer assembly that accounts for different binding affinities between and within rings.Our main finding is that deadlocka 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.Therefore, 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 majorityif not allof 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.