An integrated view of protein structure, dynamics, and function is emerging, where proteins are considered as dynamically active assemblies and internal motions are closely linked to function such as enzyme catalysis. Further, the motion of solvent bound to external regions of protein impacts internal motions and, therefore, protein function. Recently, we discovered a network of protein vibrations in enzyme cyclophilin A, coupled to its catalytic activity of peptidyl-prolyl cis−trans isomerization. Detailed studies suggest that this network, extending from surface regions to active site, is a conserved part of enzyme structure and has a role in promoting catalysis. In this report, theoretical investigations of concerted conformational fluctuations occurring on microsecond and longer time scales within the discovered network are presented. Using a new technique, kinetic energy was added to protein vibrational modes corresponding to conformational fluctuations in the network. The results reveal that protein dynamics promotes catalysis by altering transition state barrier crossing behavior of reaction trajectories. An increase in transmission coefficient and number of productive trajectories with increasing amounts of kinetic energy in vibrational modes is observed. Variations in active site enzyme−substrate interactions near transition state are found to be correlated with barrier recrossings. Simulations also showed that energy transferred from first solvation shell to surface residues impacts catalysis through network fluctuations. The detailed characterization of network presented here indicates that protein dynamics plays a role in rate enhancement by enzymes. Therefore, coupled networks in enzymes have wide implications in understanding allostericity and cooperative effects, as well as protein engineering and drug design.