Cysteine is unique among the twenty proteogenic amino acids due to the large atomic radius of its sulfur atom and the relative weakness of the corresponding S-H bond. This imbues it with remarkable nucleophilicity, facilitating spontaneous reactions even under mild conditions. The inherent nucleophilicity of a given cysteine is governed by its pK a , a value that implies the favorability of the ionization state of the thiol. Solvent-exposed cysteines have values near 8, while buried cysteines or those located in a unique protein microenvironment can range from 3 to 12. Given their variable pK a values and unique properties, cysteine residues play various functional roles in redox and nucleophilic catalysis, metal binding, environmental sensing, and structural formation. In recent years, interest has grown in targeting cysteine residues with covalent inhibitors. To overcome poor target selectivity and drug resistance, an electrophilic warhead moiety may be incorporated into a reversible submicromolar inhibitor to covalently bind a nucleophilic residue: this modification can dramatically increase therapeutic potency. Members of this class of reactive molecules are commonly referred to as targeted covalent inhibitors (TCIs) and predicting their affinity and reversibility is particularly desirable. A key step in a TCI binding and reaction landscape is the deprotonation of the cysteine thiol and the formation of the nucleophilic thiolate. Experimental exchange-rate studies have shown that the equilibrium between the protonated and deprotonated states of solvent-exposed cysteine side chains is fast (i.e., 10 • M -1 s -1 ) and that the protonation rate and pK a are well correlated. That is to say, the pK a of a particular cysteine provides the relevant information about the energy required to form the nucleophilic thiolate and, by extension, the propensity for covalent modification.