FIGURE 1.

Effect of pH perturbation on net charge of exposed Cys and electrostatic properties of molecular surface. Exposed Cys residues are significantly more polar than buried Cys residues, a consequence of the high degree of Cys polarizability. For many exposed and polar Cys residues, pK_a is close to the physiological pH (A, blue, shaded). In such cases, for a typical monoprotic acid in a physiological solution (assuming Henderson-Hasselbalch behavior), sudden negative charge switches can occur in the response to even very limited local pH shifts (A, neutral Cys for lower pH values and anionic Cys for higher pH values; note the steep transition between the two Cys forms in the shaded area). For any Cys in the protein, its interactions with other titratable groups and solvent determine the degree of reactivity of that Cys and influence its pK_a. From a computational perspective, a common way to quantify the pK_a of a residue is to calculate its deviation (ΔpK_a) from the reference pK_a value (pK_a(REF)) for that amino acid type; ΔpK_a is derived by properly accounting for all interactions with the titratable functional group, e.g. E₁, E₂, … E_n in B, where interactions with the generic titratable residues A (red circle; indicating an interacting acidic residue), B (blue circle, indicating an interacting basic residue), and t (gray circle; indicating a generic non-charged titratable residue, e.g. Thr) are shown. The ΔpK_a then allows the pK_a of a residue to be expressed as pK_a = pK_a(REF) + ΔpK_a.