Cracking the chaperone code through the computational microscope.

The heat shock protein 90 kDa (Hsp90) chaperone machinery plays a crucial role in maintaining cellular homeostasis. Beyond its traditional role in protein folding, Hsp90 is integral to key pathways influencing cellular function in health and disease. Hsp90 operates through the modular assembly of large multiprotein complexes, with their composition, stability, and localization adapting to the cell's needs.

Molecular mechanisms of chaperone-directed protein folding: Insights from atomistic simulations.

Molecular chaperones, a family of proteins of which Hsp90 and Hsp70 are integral members, form an essential machinery to maintain healthy proteomes by controlling the folding and activation of a plethora of substrate client proteins. This is achieved through cycles in which Hsp90 and Hsp70, regulated by task-specific co-chaperones, process ATP and become part of a complex network that undergoes extensive compositional and conformational variations. Despite impressive advances in structural knowledge, the mechanisms that regulate the dynamics of functional assemblies, their response to nucleotides, and their relevance for client remodeling are still elusive.