Simulation of STAT and HP1 interaction by molecular docking

Heterochromatin Protein 1 (HP1) is a major component of heterochromatin. Multiple proteins have been shown to interact with HP1 with the HP1-binding motif PxVxL/I, thereby affecting heterochromatin stability. The HP1-interacting proteins include the signal transducer and activator of transcription (STAT) protein, which can be regulated by phosphorylation on a tyrosine around amino acid 700 in the carboxyl terminus. Previous research has shown that unphosphorylated STAT (uSTAT) binds to HP1 via a PxVxI HP1-binding motif and maintains the stability of heterochromatin, while phosphorylated STAT (pSTAT) dissociates from HP1, resulting in heterochromatin disruption. To understand the theoretical basis of the biochemical observations, we employed computational modeling to investigate STAT-HP1 binding configurations and the effect of STAT phosphorylation on their interaction. Using STAT3 and HP1α protein structures for molecular docking and thermodynamic calculations, our computations predict that uSTAT homodimers have a higher affinity for HP1 and a lower affinity for DNA than pSTAT homodimers, and that phosphorylation induces a conformational change in STAT, shifting its binding preference from HP1 to DNA. The results of our modeling studies support the idea that phosphorylation drives STAT from HP1-binding to DNA-binding, suggesting a potential role for uSTAT in both maintaining and initiating heterochromatin formation.