HOXB13 is a homeodomain-containing transcription factor which normally regulates prostate cell development by controlling its gene expression via DNA binding. It is essential for prostate cell proliferation, differentiation and apoptosis to ensure the correct cell activity and function(Brechka et al. 2017). HOXB13 regulates gene expression via specific DNA sequences binding to its homeodomain (conserved DNA binding domain about 60 amino acids long) (Bürglin 2011). This model represents how HOXB13 binds to TCG containing DNA motif and the protein-DNA interactions including direct contacts as well as water-mediated interactions to facilitate binding. Interestingly, HOXB13 can bind to different DNA sequences (TCG or CAA) using distinctive thermodynamic mechanisms either driven by enthalpy or entropy. In this tour, we are going to look at how HOXB13 interacts with a double stranded DNA that contains the TCG motif and how thermodynamics is going to play an important role!