The yeast Abp1p SH3 domain is a protein domain that typically binds to proline-rich intrinsically disordered proteins (IDPs). Proline is a unique amino acid, as it is known to isomerize. ArkA is a proline rich IDP which contains the PXXP+ motif which allows it to form the Polyproline II Helix (PPII helix) secondary structure. SH3 and ArkA have a 2-step binding pathway—first they enter the encounter complex and then they reach the fully bound state. Gaussian-accelerated molecular dynamics previously revealed that all ArkA prolines spent a significant time in the cis state. The PXXP+ motif requires all prolines to be in the trans state for the PPII helix to form. Molecular dynamics simulations were utilized to observe the effect of proline isomerization on the binding of the SH3 domain and ArkA. Binding and bound simulations were run with various proline residues in cis. It was hypothesized that SH3 and ArkA would be unable to reach the bound state with a proline in the cis state. Molecular dynamics simulations revealed that despite the disruption of the PPII secondary structure, ArkA and SH3 were able to reach the encounter complex 100% of the time, and they were able to reach the fully bound state about 20% of the time. This suggests that other factors may be influencing the binding pathway between ArkA and SH3.
Rice et al. (Sun,) studied this question.