Charge Interactions Modulate the Encounter Complex Ensemble of Two Differently Charged Disordered Protein Partners of...

Disordered proteins play important roles in cell signaling and are frequently involved in protein-protein interactions. They also have a larger proportion of charged and polar residues than their folded counterparts. Here, we developed a structure-based model and applied molecular dynamics simulations to examine the presence and importance of electrostatic interactions in the binding processes of two differently charged intrinsically disordered ligands of the KIX domain of CBP. We observed non-native opposite-charged contacts in the encounter complexes for both ligands with KIX, and this may be a general feature of coupled folding and binding reactions. The ensemble of successful encounter complexes is a diverse set of structures, and in the case of the highly charged ligand, this ensemble was found to be malleable with respect to ionic strength. There are only minor differences between encounter complex ensembles for successful and unsuccessful collisions with no key interactions that appear to make the process far more productive. The energy landscape at this early stage in the process does not appear highly funneled. Strikingly we observed many native interactions that appear to reduce chances of an encounter complex being productive. Instead it appears that collectively non-native electrostatic interactions in the encounter complex increase the likelihood of productivity by holding the proteins together long enough for folding to take place. This mechanism is more effective for the more highly charged ligand.