The overall motions and atomic fluctuations of DHFR are calculated using molecular dynamics simulations to explore potential links between catalysis and dynamics in this enzyme system. Calculations of 10 ns duration were performed on three ternary complexes from the DHFR catalytic cycle: DHFR/DHF/ NADPH (DH), DHFR/THF/NADP(+) (TP), and DHFR/THF/NADPH (TH). The protein maintains a core structure very similar to the initial X-ray model, while several flexible loops undergo conformational changes. Comparison of the dynamics of the protein in the different complexes demonstrates that the ligands affect the behavior of the protein even though the ligands only differ by one to two hydrogen atoms. In particular, strong-coupled motions that appear in the reactive complex DH disappear in the product complexes, indicating that these motions may be Linked to catalysis. Furthermore, mutants, which have been observed to be debilitating to particular chemical steps in catalysis, occur with high correlation in the regions of the protein structure observed in our simulations to participate in highly coupled motions. We conclude from our analysis that the mutants could be affecting catalysis by altering the protein dynamics.