The Effect of The Protein Environment
When a protein folds, the titratable amino acids in the protein are transferred from a solution-like environment to an environment determined by the 3-dimensional structure of the protein. For example, in an unfolded protein an aspartic acid typically is in an environment which exposes the titratable side chain to water. When the protein folds the aspartic acid could find itself buried deep in the protein interior with no exposure to solvent.
Furthermore, in the folded protein the aspartic acid will be closer to other titratable groups in the protein and will also interact with permanent charges (e.g. ions) and dipoles in the protein. All of these effects alter the pKa value of the amino acid side chain, and pKa calculation methods generally calculate the effect of the protein environment on the model pKa value of an amino acid side chain .
Typically the effects of the protein environment on the amino acid pKa value are divided into pH-independent effects and pH-dependent effects. The pH-independent effects (desolvation, interactions with permanent charges and dipoles) are added to the model pKa value to give the intrinsic pKa value. The pH-dependent effects cannot be added in the same straight-forward way and have to be accounted for using Boltzmann summation, Tanford-Roxby iterations or other methods.
The interplay of the intrinsic pKa values of a system with the electrostatic interaction energies between titratable groups can produce quite spectacular effects such as non-Henderson-Hasselbalch titration curves and even back-titration effects. pKaTool provides an easy interactive and instructive way of playing around with these effects.
The image below shows a theoretical system consisting of three acidic residues. One group is displaying a back-titration event (blue group).
Read more about this topic: Protein P Ka Calculations
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