SH3 domains are a common site for protein-protein interactions that bind to regions of intrinsically disordered proteins, such as ArkA, to carry out cellular processes. ArkA consists of two segments: segment 1, which is stably bound to its domain due to its proline-rich motif; and segment 2, which is an unstable, flexible structure due to the lack of this motif. This study aimed to analyze the unbinding behavior and rates of ArkA from its domain using different variations of the peptide with varying lengths or alternative sequences. Molecular Dynamics (MD) simulations concluded that the binding of segment 1 is not affected by the absence of segment 2, as it stays bound nearly 100% of the time; however, segment 2 only stays bound approximately 60% of the time. Segment 2’s inability to remain fully bound to its partner domain, AbpSH3, allowed us to measure the rates at which it partially unbinds and fully unbinds from AbpSH3. MD simulations were performed to generate the binding surface distances of ArkA from AbpSH3, and computer programming was used to visualize and calculate the behavior and kinetic rates of the peptide. The results show that entering the encounter complex of the binding pathway doesn’t guarantee the full unbinding of the ArkA peptide and highlight the significant role segment 1 plays in keeping ArkA bound to the AbpSH3 domain.
Poaquiza et al. (Sun,) studied this question.