Intrinsically disordered peptides (IDPs), which lack stable structures under physiological conditions, play important roles in cellular processes such as signaling, regulation, and organization. ArkA, a yeast-derived IDP, commonly binds to the AbpSH3 domain, a protein-binding domain found in all Eukaryotes. The binding pathway goes through an intermediate state, the encounter complex, which is mediated by favorable electrostatic interactions between charged residues and non-specific hydrophobic interactions. The strength of electrostatic interactions can be influenced by salt, disrupting the formation of the encounter complex. We used molecular dynamics (MD) simulations to model the binding of the ArkA peptide to the AbpSH3 domain, along with the fully bound state, in high salt concentrations (800 mM). The observed effects of ionic strength on the flexibility, electrostatic interactions, and kinetics of the ArkA-AbpSH3 binding complex suggest that the encounter complex is the part of the binding pathway most disrupted by a high salt concentration. Investigating the role of salt in the ArkA-AbpSH3 binding pathway highlights how non-specific, long-range electrostatic interactions can stabilize key intermediate states that are critical for IDP binding.
Cardoso et al. (Sun,) studied this question.