We have studied the binding of camphor in the active site of cytochrome P450cam with density functional theory (DFT) calculations. A strong hydrogen bond (>6 kcal/mol) to a tyrosine residue (Tyr96) is observed, that may account for the high specificity of the reaction taking place. The DFT interaction energy is well reproduced by QM/MM calculations, which allows for application of QM/MM to the catalytic cycle of cytochrome P450s. The substrate is distorted considerably due to the presence of the protein environment, which however does not have a large impact on the strong hydrogen bonding interactions. © 2004 Elsevier B.V. All rights reserved.