We have performed a 800 ps molecular dynamics simulation of bovine pancreatic trypsin inhibitor (BPTI) in water coupled to a pressure bath at 1, lO,OOO, 15,000, and 20,000 bar. The simulation reproduces quite well the experimental behavior of the protein under high pressure. The protein keeps its globular form, but adopts a different conformation with a very small reduction in volume. Some residues in the hydrophobic core become exposed to water and a large part of the secondary structure of the protein, (60% of the sheet structure a n d 40% of the helical structure) is denatured between 10 and 15 kbar. This is in good agreement with experimental data (Goossens, K., et al. Eur. J. Biochem, 236254-262,1996) that show denaturation of BPTI between 8 and 14 kbar. A further increase of the pressure results in a freezing of the protein as deduced from the large decrease of the mobility of the residues. During the simulation, the normal structure of water changes from an ice Ih-like to an ice VIlike structure, while keeping the liquid state. The driving force of the high pressure induced conformational transition seems be the higher compressibility of the water compared with the protein. This produces a change in the solvent properties and leads to penetration of the solvent into the hydrophobic core.