Saturday, April 30, 2011

Deconstructing protein phase diagrams

In the process of coming up with new exam questions for my undergraduate thermodynamics and condensed matter course I came across the following pressure-temperature phase diagram for the protein ribonuclease A at pH 2.0.
It is taken from a 1995 Biochemistry paper and I came across it in the wonderful text by Dill and Bromberg.
[Aside: I wondered if the water freezing was an issue but all along the curve the solvent water is liquid because dP/dT is negative for the liquid-solid line of pure water].

Natural scientific questions are:
  • What are the mechanisms of "cold" and pressure-induced denaturation? 
  • What are the associated changes in protein structure?
  • Is this a generic type of phase diagram for proteins?
  • What role does water and hydrophobic interactions play?
A nice review article from 2002 by Smeller discusses how these diagrams are indeed generic and their shape can be understood in terms of a simple thermodynamic theory due to Hawley in 1971.
One simply expands the Gibbs free energy change to second order in T and P relative to some reference pressure P0 and temperature T0,
The pressure induced denaturation can then lead to a volume contraction. This is explained in microscopic terms in a 1998 PNAS paper by Hummer et al.,

The pressure dependence of hydrophobic interactions is consistent with the observed pressure denaturation of proteins

which shows
Pressure-denatured proteins, unlike heat-denatured proteins, retain a compact structure with water molecules penetrating their core. 

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