Microscopic Mechanism for Cold Denaturation

We elucidate the mechanism of cold denaturation through constant-pressure simulations for a model of hydrophobic molecules in an explicit solvent. We find that the temperature dependence of the hydrophobic effect induces, facilitates, and is the driving force for cold denaturation. The physical mechanism underlying this phenomenon is identified as the destabilization of hydrophobic contact in favor of solvent-separated configurations, the same mechanism seen in pressure-induced denaturation. A phenomenological explanation proposed for the mechanism is suggested as being responsible for cold denaturation in real proteins.

Figure 1

Normalized distribution of the radius of gyration $R_G$ at three temperatures: $T=0.25$, $T=0.21$, and $T=0.17$. Inset: The temperature dependence of $R_G$ of the protein.

Figure 2

Hydrogen bond energy per water molecule for shell and bulk water. Inset: Absorbed energy to accommodate the protein at different temperatures. The shell is defined by water molecules whose distance to the protein is less than 2.5 in units of $R_{\mathrm{H}}$.

Figure 3

Characteristic configurations of a protein in cold water ($T=0.15$ and $T=0.17$), at an intermediate temperature ($T=0.21$), and in hot water ($T=0.25$). The distance of highlighted (shell) water molecules to the protein is less than 2.5 in units of $R_{\mathrm{H}}$. In cold water, the monomers are typically surrounded by clathratelike cages.