(540a) The Free Energy of a Salt Bridge From Simulations

Understanding when and how salt bridges are stabilizing is still an open question. Researchers have argued that in the core of a protein where there is no charge screening, salt bridges will stabilize proteins more than on the surface of proteins. However, mutagenesis studies have shown that to not always be the case. One key question is how well the different ionic amino acids(K,E,R,D) pair without any influence from the protein and how their solvation affects this. We used state of the art free energy techniques, replica exchange metadynamics, to quantify both the free energy of forming salt bridges between the different amino acids as well as the free energy of desolvating them. Combining these two terms into a thermodynamic cycle gives insight into how the local environment affects pairs. Specifically, we've found that the desolvation is as important, and more important in some cases, than the formation of salt bridges. The differences in free energy of salt bridges can be explained by a combination of the differences in geometry and solvation. Additionally, we've examined pairs on hundreds of proteins from the protein data bank (PDB) in order to compare our results with what is observed in Nature. Our results match the ranking of the salt bridges the PDB. Finally, we've created a probability based free energy surface from the PDB data and compared it with our simulation based free energy surface.