On the molecular origin of cold denaturation of globular proteins

Abstract

A polypeptide chain can adopt very different conformations, a fundamental distinguishing feature of which is the water accessible surface area, WASA, that is a measure of the layer around the polypeptide chain where the center of water molecules cannot physically enter, generating a solvent-excluded volume effect. The large WASA decrease associated with the folding of a globular protein leads to a large decrease in the solvent-excluded volume, and so to a large increase in the configurational/translational freedom of water molecules. The latter is a quantity that depends upon temperature. Simple calculations over the -30 to 150 °C temperature range, where liquid water can exist at 1 atm, show that such a gain decreases significantly on lowering the temperature below 0 °C, paralleling the decrease in liquid water density. There will be a temperature where the destabilizing contribution of the polypeptide chain conformational entropy exactly matches the stabilizing contribution of the water configurational/translational entropy, leading to cold denaturation.

A fully atomistic computer simulation study of cold denaturation of a β-hairpin

“…Therefore, this reduction of the translational entropy of the tip4p water becomes less severe at T low, thereby effectively decreasing the hydration free-energy cost of the unfold state for cold denaturation. Consistent with previous studies [28][29][30][31] , this temperature-dependent behaviour of the translational water entropy seems to be a plausible interpretation of the cold-denaturation phenomenon of MrH1. As summarized in Table 2, on unfolding, the enthalpic contributions from protein (DU protein and DU water F!D terms can be responsible for decreasing the system enthalpy on cold denaturation.…”

“…Therefore, the lack of such orientational ordering of water at low temperatures precludes a possibility of enhanced water hydrogen-bond networks near hydrophobic residues. Instead, as proposed in earlier studies [28][29][30][31] , the entropy loss on cold denaturation is more likely attributed to the effect of translational entropy of water coexisting with proteins.…”

Temperature-dependent solvation modulates the dimensions of disordered proteins

“…The decreasing solvation free energy of the chain with increasing temperature, which collapses the unfolded state, might also be expected to stabilize the folded protein. Indeed, the resultant destabilization as the temperature is lowered results in the "cold unfolding," which can be observed for certain proteins (35,37,38,(57)(58)(59)(60). However, at higher temperatures, unfolding is driven by the large increase in chain entropy on unfolding (61); at these temperatures, the unfolded chain may nonetheless continue to collapse (driven by unfavorable solvation free energy) because the variation in configurational entropy for a reduction in chain dimensions is much smaller than that for folding.…”

A view on the dogma of hydrophobic imperialism in protein folding

“…I have assumed that ΔE a (H 2 O) ≈ 0 with the following reasoning (Graziano, 2010;Riccio & Graziano, 2011). In the interior of the N-state, a lot of van der Waals contacts and H-bonds are turned on.…”

“…I have shown that to shed light on the conformational stability of a globular protein possessing two thermodynamic states, the N-state (representative of the ensemble of native, folded conformations) and the D-state (representative of the ensemble of unfolded conformations), it is useful to analyze the following thermodynamic cycle (Graziano, 2010): where N represents the N-state and D represents the D-state; ΔG d is the Gibbs energy change associated with protein unfolding (i.e. denaturation) in water; ΔG conf is the Gibbs energy change associated with protein unfolding in the gas phase:…”