The hydrolysis of adenosine 5'-triphosphate (ATP) at the active site of actin has been studied using density functional calculations. The active site is modeled by the triphosphate tail of ATP, an Mg cation, surrounding water molecules, and the nearby protein residues. Four reaction paths have been followed by constraining coordinates that allow phosphate stretching, nucleophilic attack of the catalytic water, and OH- formation via water deprotonation. The lowest-energy barrier (21.0 kcal/mol) is obtained for a dissociative reaction where the terminal phosphate breaks on approaching the catalytic water, followed by proton release via a proton wire mechanism. A higher barrier (39.6 kcal/mol) results for an associative reaction path where OH- is formed first, with a pentacoordinated phosphorus atom (P-O distances 2.1 angstrom). Stretching the terminal bridging P-O bond results in bond rupture at 2.8 angstrom with an energy barrier of 28.8 kcal/mol. The residues Gln 137 and His 161 are not important in the reactions, but insight into their roles in vivo has been obtained. The favored coordination of the end products H2PO4- and ADP(3-) includes a hydrogen bond and an O-Mg-O bridge between the phosphates as well as a hydrogen bond between H2PO4- and the Serl4 side chain. The total energy is 2.1 kcal/mol lower than in the initial reactants. Classical simulations of ATP- and ADP(.)Pi-actin show few hydrolysis-induced differences in the protein structure, indicating that phosphate migration is necessary for a change in conformation.