Effect of chaperone-client interaction strength on Hsp70-mediated protein folding

Protein folding in crowding cellular environment often relies on the assistance of various chaperones. Hsp70 is one of the most ubiquitous chaperones in cells. Previous studies showed that the chaperone-client interactions at the open state tend to remodel the protein folding energy landscape and direct the protein folding as a foldase. In this work, we further investigate how the chaperone-client interaction strength modulates the foldase function of Hsp70 by using molecular simulations. The results showed that the time of substrate folding (including the whole folding step and substrate release step) has a non-monotonic dependence on the interaction strength. With the increasing of the chaperone-client interaction strength, the folding time decreases first, and then increases. More detailed analysis showed that when the chaperone-client interaction is too strong, even small number of chaperones-client contacts can maintain the substrate bound with the chaperone. The sampling of the transient chaperones-client complex with sparse inter-molecule contacts makes the client protein have chance to access the misfolded state even it is bound with chaperone. The current results suggest that the interaction strength is an important factor controlling the Hsp70 chaperoning function.