Protonation state of amino acid residue and pKa calculations

Ka (acid dissociation constant) is a quantitative measure of the strength of an acid in solution. In aqueous solution, the equilibrium of acid dissociation can be written symbolically as:

                                          \mathrm {HA+H_{2}O\rightleftharpoons A^{-}+H_{3}O^{+}}
                                 K_{\mathrm {a} }=\mathrm {\frac {[A^{-}][H_{3}O^{+}]}{[HA][H_{2}O]}}
                       \ \mathrm {p} K_{\mathrm {a} }=-\log _{10}K_{\mathrm {a} }

Following is the list of titratable amino acid and their model pKa values.

 

Amino Acid pKa
Asp (D) 3.9
Glu (E) 4.3
Arg (R) 12.0
Lys (K) 10.5
His (H) 6.08
Cys (C) (–SH) 8.28
Tyr (Y) 10.1

The pKa value of the titratable amino acids in a 3D protein structures deviates from the model values (inferred from free compounds in that are similar to the side chains of amino acids). When a protein takes it 3D shape, the chemical environment of titratable amino acids in the protein is changed from solution-like environment to an environment determined by the 3-dimensional structure of the protein. For example, in an unfolded protein an amino acid typically is in an environment which exposes the titratable side chain to water. When the protein folds a residue could find itself buried deep in the protein interior close to other amino acids and ions, with no exposure to solvent. 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.