The environment of a dissociable group affects its pKa. The pKa values of the R groups of free amino acids in aqueous solution (Table 3–1) thus provid

The environment of a dissociable group affects its pK_a. The pK_a values of the R groups of free amino acids in aqueous solution (Table 3–1) thus provide only an approximate guide to the pK_a values of the same amino acids when present in proteins. A polar environment favors the charged form (R—COO^– or R—NH₃⁺), and a nonpolar environment favors the uncharged form (R—COOH or R—NH₂). A nonpolar environment thus raises the pK_a of a carboxyl group (making it a weaker acid) but lowers that of an amino group (making it a stronger acid). The presence of adjacent charged groups can reinforce or counteract solvent effects. The pK_a of a functional group thus will depend upon its location within a given protein. Variations in pK_a can encompass whole pH units (Table 3–2). pK_a values that diverge from those listed by as much as 3 pH units are common at the active sites of enzymes. An extreme example, a buried aspartic acid of thioredoxin, has a pK_a above 9—a shift of more than 6 pH units!