B) Energetic landscape of the model in (A). Acidic GKs are indicated in red, basic GKs in blue and the non-gatekeeped energy landscape in grey. GKs thermodynamically destabilize and kinetically slow down the folding reaction, resulting in higher energies for N and TN⇋U. Acidic residues have a similar effect on the aggregated state, decreasing aggregate formation kinetics and thermodynamic stability. Basic residues on the other hand, only marginally affect aggregate stability and mostly work through deceleration of the aggregation process through an increase in TU⇋A energy. Through specifically binding positive residues, Hsp70 slows aggregate formation kinetics for positively gatekeeped APRs. Hence, Hsp70 increases GK potential of basic residues, preventing aggregation and allowing for a stable native fold. 