Rising global temperatures require innovative measures to reduce atmospheric concentrations of CO2. The most successful carbon capture technology on Earth is the enzymatic capture of CO2 and its sequestration in the form of glucose. Efforts to improve upon or mimic this naturally occurring process will require a rich understanding of protein-CO2 interactions. Toward that end, extensive all-atom molecular dynamics (MD) simulations were performed on the CO2-utilizing enzyme phosphoenolpyruvate carboxykinase (PEPCK). Preliminary simulations were performed using implicit and explicit solvent models, which yielded similar results: arginine, lysine, tyrosine, and asparagine enhance the ability of a protein to bind carbon dioxide. Extensive explicit solvent simulations were performed for both wild-type PEPCK and five single-point PEPCK mutants, revealing three prevalent channels by which CO2 enters (or exits) the active site cleft, as well as a fourth channel (observed only once), the existence of which can be rationalized in terms of the position of a key Arg residue. The strongest CO2 binding sites in these simulations consist of appropriately positioned hydrogen bond donors and acceptors. Interactions between CO2 and both Mn2+ and Mg2+ present in PEPCK are minimal due to the stable protein- and solvent-based coordination environments of these cations. His 232, suggested by X-ray crystallography as being a potential important CO2 binding site, is indeed found to be particularly "CO2-philic" in these simulations. Finally, a recent mechanism, proposed on the basis of X-ray crystallography, for PEPCK active site lid closure is discussed in light of the MD trajectories. Overall, the results of this work will prove useful not only to scientists investigating PEPCK, but also to groups seeking to develop an environmentally benign, protein-based carbon capture, sequestration, and utilization system.