N=Native fold, U=unfolded state, A=aggregated state, T=transition state. A) Effects of GK placement on the energetics of the native, unfolded and aggregated states. GKs generally come with a cost to the native fold stability, with negative GKs being more destabilizing on average owing to their shorter sidechains and resulting increased burial costs (a). On the other hand, acidic residues more effectively destabilize the aggregated state than basic residues (b). Consequently, structural constraints in the native state may lead to APRs that are inadequately protected by their basic GKs. Hsp70 specifically recognizes these APRs through their inadequate GKs, and effectively compensates for the difference in destabilization of the aggregated state between basic and acidic residues (c). 