| Summary: | Inside the cell, proteins fold and perform complex functions through global structural rearrangements. For proper function, they need to be at the brink of instability to be susceptible to small environmental fluctuations yet stable enough to maintain structural integrity. These apparently conflicting properties are exhibited by systems near a critical point, where distinct phases merge. This concept goes beyond previous studies that propose proteins have a well-defined folded and unfolded phase boundary in the pressure-temperature plane. Here, by modeling the protein phosphoglycerate kinase (PGK) on the temperature (T), pressure (P), and crowding volume-fraction (ϕ) phase diagram, we demonstrate a critical transition where phases merge, and PGK exhibits large structural fluctuations. Above the critical temperature (T_{c}), the difference between the intermediate and unfolded phases disappears. When ϕ increases, the T_{c} moves to a lower T. With experiments mapping the T-P-ϕ space, we verify the calculations and reveal a critical point at 305 K and 170 MPa that moves to a lower T as ϕ increases. Crowding shifts PGK closer to a critical line in its natural parameter space, where large conformational changes can occur without costly free-energy barriers. Specific structures are proposed for each phase based on the simulation.
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