Entropic effects of protein stability

Entropy–enthalpy compensation is observed in many reactions, particularly for polymeric biomolecules that often involve large changes in entropy and enthalpy. The imperfect cancelation of entropy and enthalpy dictates many biophysical characteristics, such as protein thermodynamic stability and the free energy barrier for protein folding. Here, we use coarse-grained molecular dynamics simulations and analytical model analysis to examine how modifying the proteins sequence (e.g., by single point mutations) or the structure (e.g., by tethering of a conjugate) may affect the thermodynamic stability of the protein.

We found that a mutation that involves the breaking of long-range contacts may lead to an increase in the unfolded state entropy. In accord, we found that tethering of a conjugate mostly affects the unfolded state of the protein by eliminating formation of some residual contacts, which leads to an increase in the entropy of the unfolded state. In both cases, the increase in the configurational entropy of the unfolded sate is larger than the increase in enthalpy due to the loss of residual contacts. This leads to stabilization of the unfolded state and consequently to an overall destabilization of the protein. Our results are in line with experimental results and are further supported by bioinformatic analysis.

Citations:

(1) Bigman, L. S.; Levy, Y. Entropy-Enthalpy Compensation in Conjugated Proteins. Chem. Phys. 2018, 514, 95–105.

(2) Bigman, L. S.; Levy, Y. Stability Effects of Protein Mutations: The Role of Long-Range Contacts. J. Phys. Chem. B 2018.