Question

Do you expect a pro rightarrow Gly multation in a surface-loop region of a globular protein to be stabilizing or destablizing? Assume the mutual folds to a native-like conformation. Explain your answer in terms of the predicted enthalpic and entropic effects of the mulation on the deltaG for protein folding compared to deltaG of the folding for the wild-type protein

Answer 1

Pro-Gly mutation in a surface-loop region of a globular protein is stabilizing.

Overall, protein folding is a process controlled by thermodynamic and kinetic parameters. interactions controlling the formation of secondary and tertiary structure, such as hydrogen bons, electrostatic and hydrophobic forces turn folding into a thermodynamically favorable process. The free energy profiles show the acquisition of the native structure from its unfolded ensemble via a transition state ensemble, resulting in a global decrease of the free energy of the system.

Entropic and enthalpic determine the free energy of the system according to the following equation:

$\Delta G=\Delta H-T\Delta S$

The entropic contribution to folding is generally unfavorable because the attainment of a single ordered structure implies the loss of many initially unstructured conformations. however, the hydrophobic effect reduces the entropic penalty for folding, since water molecules, ordered around hydrophobic residues exposed to solvent in the unfolded ensemble, gain entropy upon folding.

Favorable enthalpic terms include the formation os stabilizing native interactions, such as electrostatic effects, hydrophobic forces, hydrogen bonds and Van der Waals interactions.

Drag the terms:

1) The stabilization is likely to be small because side-chain solvation is predicted to be similar in both the folded and unfolded states. $\Delta$S protein changes the most due to the conformational flexibility of Gly compared to Pro.

2) Gly will stabilize both the folded and unfolded states; however, it will stabilize the unfolded state more due to the dramatic increase in conformational entropy of the unfolded state as a result of this mutation.

3) The destabilization of the unfolded state for the mutant means that $\Delta$Gfolding(mut) less than $\Delta$Gfolding(wt); thus, the mutation is stabilizing