SH3 binding pathway and kinetics in the presence of salt.

Abstract

Protein-protein interactions are involved in a wide range of cellular processes, like cell signaling, in which these interactions often bind to intrinsically disordered proteins. SH3 domains are common protein interaction domains which are typically negatively charged and typically bind proline-rich disordered segments, which are positively charged. This project focuses on the role of electrostatics in the binding pathway of the yeast protein Abp1 SH3 domain (AbpSH3) and the intrinsically disordered peptide ArkA. We are investigating the binding pathway by simulating ArkA-AbpSH3 binding using molecular dynamics in the presence of sodium chloride, which serves to screen electrostatic interactions. Previous simulations in the absence of salt showed that ArkA initially forms a disordered encounter complex with AbpSH3 before reaching the fully bound state. In the absence of salt, the encounter complex, characterized by many transient non-specific electrostatic interactions, forms rapidly followed by a slower transition to the fully bound state. The addition of 800 mM sodium chloride leads to a slower encounter complex formation and a decrease in electrostatic contacts. Screening of long-range electrostatic interactions could also disrupt electrostatic steering to the binding surface during the initial encounter complex formation. Simulating the binding between ApbSH3 and ArkA in the presence of salt can provide insight into the role of electrostatics in SH3 binding in general and can be compared to experimental data on AbpSH3 binding at different salt concentrations.