Abstract
In the cell, proteins fold and perform complex functions through global structural rearrangements. Function requires a protein to be at the brink of stability to be susceptible to small environmental fluctuations, yet stable enough to maintain structural integrity. These apparently conflicting behaviors are exhibited by systems near a critical point, where distinct phases merge-a concept beyond previous studies indicating proteins have a well-defined folded/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 point, the difference between the intermediate and unfolded phases disappears. When ϕ increases, the critical point moves to lower T c. We verify the calculations with experiments mapping the T-P-ϕ space, which likewise reveal a critical point at 305 K and 170 MPa that moves to lower T c as ϕ increases. Crowding places PGK near 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 simulation.
Highlights
Complex processes in nature often arise at a transition between order and disorder [1,2,3,4]
Even though critical behavior of proteins has been previously suggested [7,8,9], a critical point where one of these abrupt transitions disappears at Tc and Pc has not been demonstrated
We investigate the conformations of phosphoglycerate kinase (PGK), a large, 415amino-acid, two-domain protein
Summary
Complex processes in nature often arise at a transition between order and disorder [1,2,3,4]. We use pressure P, temperature T, and the crowderexcluded volume fraction φ to map PGK’s folding energy landscape [12,18] and its critical regime on the T-P-φ phase diagram. Since folded proteins contain heterogeneously distributed small, dry cavities due to imperfect packing of their quasifractal topology [21,22,23], high pressure induces unfolding by introducing water molecules (as small granular particles) into the cavities in protein structures. This process reduces the overall solventaccessible volume of the unfolded protein [24].
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