The enzyme phosphodiesterase 6 (PDE6) is a critical component of the visual signaling pathway and functions to convert cGMP to GMP. The ability of PDE6 to affect cellular cGMP levels leads to deactivation of cGMP-gated ion channels in both rod and cone cells. PDE6 has been difficult to structurally characterize experimentally, though the structures of the closely related PDE5 and a PDE5/6 chimera have been determined by X-ray crystallography. In this work, we employ a computational approach to study the dynamics of the catalytic domains of PDE6, PDE5, and the PDE5/6 chimera. Through equilibrium molecular dynamics (MD) simulations, we identify a region of PDE6 (α12) to be correlated to distal regions of the enzyme (H- and M-loops), which surround the catalytic center. These correlations are not observed for PDE5, and we speculate that these unique motions in PDE6 may relate to the high catalytic efficiency of PDE6 and the requirement for an endogenous inhibitory subunit (Pγ). We further investigate the ligand binding pathways and energetics by enhanced sampling simulations (metadynamics) using the inhibitor sildenafil and GMP. The energetics and pathways of ligand binding are consistent with the high efficiency of PDE6 and further implicate the α12 region as an important regulatory element for PDE6 functional dynamics.