Thermodynamic Considerations of Protein Structure
Thermodynamics provides a useful framework for calculation of equilibrium constants of reactions. This also applies to the “reaction” of protein denaturation. Consider a protein denaturing from a specific native conformation, N, to any of a great many nonspecific, random conformations characteristic of denatured proteins, D. The reaction can be described by an equilibrium constant that relates the amount of the protein found in each of the two states if the system has reached equilibrium,
Thermodynamics provides a way of calculating Keq as
where ∆G is the change in Gibbs free energy; R is the universal gas constant; T is the absolute temperature in degrees Kelvin; ∆H is the enthalpy change of the reaction, which in biological systems is equiva-lent to binding energy when volume changes can be neglected; and ∆S is the entropy change of the reaction. Entropy is related to the number of equivalent states of a system. The state of a protein molecule confined to one conformation without any degrees of freedom possesses much lower entropy than a denatured protein that can adopt any of a great number of conformations all at the same energy. For clarity, we will neglect the contributions of the surrounding water in further considera-tions, but in physically meaningful calculations these too must be included.
Let us examine why proteins denature when the temperature is raised. If the protein is in the folded state at the lower temperature, Keq is less than 1, that is,
As the temperature increases, neglecting the small temperature-dependent changes that occur in the interaction energies and entropy change, the term T∆S increases, and eventually exceeds ∆H. Then the equilibrium shifts to favor the denatured state.
The temperature dependence of the denaturing of proteins provides the information necessary for determination of ∆Η of denaturing. It is very large! This means that ∆S for denaturing is also very large, just as we inferred above, and at temperatures near the denaturing point, the
difference of these two large numbers barely favors retention of the structure of the protein. Hence the binding energies of the many interactions that determine protein structure, hydrogen bonds, salt bridges, dipole-dipole interactions, dispersion forces, and hydrophobic forces just barely overcome the disruptive forces. Thus we see the value of the peptide bond. If rotations about the C-N bond were not re-stricted,the increased degrees of freedom available to the protein would be enormous. Then the energy and entropy balance would be tipped in the direction of denatured proteins.
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