Water penetration into the hydrophobic interior of proteins has been postulated to be a primary force driving pressure-induced denaturation of proteins. The water penetration model is supported by several theoretical and simulation studies, although its direct evidence is lacking. In this study, 1 mu s all-atom molecular dynamics simulations of ubiquitin in explicit water at high and low pressures are performed to examine the water penetration model. The high-pressure simulation starts from a crystal structure at atmospheric pressure and successfully reproduces the main characteristics of a high-pressure structure obtained by NMR. Water penetrates into a specific hydrophobic core of the protein and is ejected from the interior several times. The structural transition results from the relative stabilization of a preexisting metastable structure by applying pressure. A time correlation analysis demonstrates that the transition is accompanied by the penetration of water within a time scale comparable to the relaxation time of water itself. Simultaneous water penetration only occurs above a certain high pressure.