SH3 domains are common interaction domains in the human body that foster cellular communication through protein-protein interactions. SH3 domains often bind to intrinsically disordered proteins (IDPs). The mechanisms of these interactions are difficult to study experimentally, so Molecular Dynamics (MD) simulations were used to support experimental data and analyze the interactions between AbpSH3, an SH3 domain found in yeast, and the disordered peptide, ArkA. ArkA contains several positively charged residues and AbpSH3 has a net negative charge enabling electrostatic contacts to stabilize the ArkA-SH3 complex. Adding salt screens these electrostatic contacts. Na+ interacts with the negative residues of the SH3 domain, and Cl- with the positive residues of ArkA, inhibiting intermolecular contacts from forming. Our lab used MD simulations to investigate how salt influences binding at the atomic level. We found that Na+ spends more time in contact with negatively charged SH3 residues compared to Cl- with positively charged residues. To determine whether this difference is related to the size of the ion, we ran simulations with KCl instead of NaCl, since K is bigger than Na. We found that the frequency of K+ binding to the SH3 domain was half as frequent as Na+ binding to the SH3 domain. This verified our theory of size being the main factor. However, there were other factors as well that influenced the less frequent binding of K+. We also found that in the bound complex interactions between the peptide and domain can be replaced by interactions with salt ions. In the future we will investigate how salt affects the binding process, including the binding rate.

Effect of salt on the ArkA-SH3 complex

ACS Fall 2021

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