Most proteins in the cell are only marginally stable, to allow their flexibility and plasticity and ultimately their easy recycling. The downside is the sensitivity of the structure of proteins to perturbations, in the form of environmental stresses and/or mutation, and the ensuing aggregation, which is in general toxic to all organisms.

To counteract protein aggregation, all organisms are endowed with a Protein Quality Control system composed of “chaperone” proteins that can reverse the process and allow previously aggregated proteins to be functional again. Importantly, chaperones are molecular machines, that use the energy from ATP to perform their function.

In this talk I will focus on the Hsp70 protein, which is the central hub of Protein Quality Control, and show modeling at multiple scales, together with in bulk and single-molecule experiments has allowed us to understand the individual steps of its mechanism of action.

The emerging picture portraits a proteome whose structural composition is not purely dictated by thermodynamic equilibrium, with relevant consequences for our understanding of protein evolution.