Structure-function relationship of the molecular chaperone DNAJB6b at atomistic resolution

Proteins must fold and assemble correctly to maintain cellular function. When this process fails, aberrant aggregation and phase separation can lead to disease. This thesis investigates the molecular mechanisms by which the molecular chaperone DNAJB6b suppresses aggregation of polyglutamine rich proteins, with a focus on understanding how sequence features and conformational dynamics regulate chaperone activity. Using a combination of all atom and coarse grained molecular dynamics simulations, this work dissects the conformational landscape of DNAJB6b and its interactions with aggregation prone substrates. Particular attention is given to the autoinhibitory mechanism of DNAJB6b and to how specific residues stabilize this regulatory state, as well as how this autoinhibition is released upon interaction with client proteins. In parallel, a coarse grained modeling framework is developed and calibrated against all atom simulations to study polyglutamine aggregation across length and time scales beyond the reach of atomistic models, and to examine how chaperones influence these processes. Together, these approaches provide molecular insight into how chaperones modulate protein aggregation and phase behavior, and establish computational strategies for studying sequence dependent aggregation mechanisms. The results contribute to a mechanistic understanding of proteostasis and offer a foundation for exploring chaperone dependent pathways in protein misfolding diseases.