Characterizing the long-range and short-range interactions stabilizing a model SH3 recognition complex

SH3 domains are common recognition domains found in many protein complexes of all eukaryotes. Their regulatory functions are involved in cell proliferation, differentiation, cytoskeleton modification and are vital for cellular communication. We have used Molecular Dynamics (MD) simulations to computationally model a common interaction between the AbpSH3 domain and the intrinsically disordered peptide, ArkA. This work is in collaboration with and in support of previous experimental studies of the complex aimed to characterize the binding pathway including NMR, ITC, and chemical denaturation. Specifically, my work focuses on the long-range electrostatic interactions involved in stabilizing the bound AbpSH3- ArkA complex. Previous experimental results have concluded that the addition of sodium chloride to the complex decreases the free energy difference between the unbound and bound states. To further investigate this destabilization of the bound state by salt, we have simulated the bound complex in the presence and absence of sodium chloride, which serves to screen electrostatic interactions. I have included computational work comparing the native intermolecular complex to a hybrid construct used in experimental techniques which connects the domain and peptide with a flexible linker. Combining the experimental and computational results, we have determined important electrostatic interactions present in the bound AbpSH3- ArkA complex contributing to the complete binding pathway