Figure 1.

The importance of the intrinsic pK_a when redesigning protein pK_a values. In the top panel an acid with an intrinsic pK_a of 4.0 is inserted so that it interacts with the target group (intrinsic pK_a 6.0) with an interaction energy of 2.3 kT/e. This results in the pK_a of the target residue being elevated 1.0 unit. Similarly, in the bottom panel we insert an acid with an intrinsic pK_a value of 8.0 that interacts with the target acid with an interaction energy of 2.3 kT/e. However, since the intrinsic pK_a value of the inserted group is larger than that of the target residue, the pK_a value of the target group remains 6.0, whereas the pK_a value of the inserted group is elevated by 1.0 units.