The hydride transfer reaction catalyzed by the enzyme dihydrofolate reductase is simulated with a hybrid quantum/classical molecular dynamics method. Electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme, are included in these simulations. The free energy profile is generated as a function of a collective reaction coordinate. The structure, hydrogen bonding, electrostatic interactions, and correlated motions are analyzed along the collective reaction coordinate (i.e., at the reactant, transition state, and product). The analysis of hydrogen bonding and electrostatics provides insight into the impact of conformational changes on the energetics of the reaction. A charge deletion scheme is used to quantify the electrostatic contributions of each residue along the collective reaction coordinate and to identify the key residues that influence the changes in the electrostatic energy during the reaction. Analysis of the correlated motions in the enzyme, cofactor, and substrate reveals significant changes in the correlations during the reaction and identifies the correlated motions most relevant to hydride transfer. These analyses have important implications for protein engineering and drug design.