Experimental methods for determining the pK a value of a cysteine can involve kinetic assays, spectrophotometric titrations, or NMR spectroscopy; however, in a purely computational in silico screen of potential covalent modifiers, the ability to rapidly and accurately probe the reactivity of a target cysteine under various conditions is highly desirable. Theoretical approaches motivated by the thermodynamic cycle given in Figure , present a compelling alternative to experiment and can often be seamlessly integrated alongside existing computational free energy workflows.