Deciphering the processes by which proteins recognize and bind to DNA is critical in our quest to understand cellular functions. To reach this goal, a collaboration with the group of Stephen Sligar, UIUC, explored the factors involved in protein-DNA recognition using hydrostatic pressure to perturb the binding of the BamHI endonuclease to cognate DNA. Our joint resulting publication outlines a new technique of high-pressure gel mobility shift analysis to test the effects of elevated hydrostatic pressure on the binding of BamHI (so-called restriction enzyme) to a specific DNA sequence. Upon application of a hydrostatic pressure of 500 bar, recognition between BamHI and the DNA sequence was weakened nearly 10-fold, suggesting an important role of water. An advanced 65,000 atom nanosecond molecular dynamics simulations with NAMD, at both ambient and elevated pressures, complemented the experiments and revealed how water-mediated interactions between BamHI and DNA control sequence recognition.