Since the early work of Tanford and Kirkwood, several methods have emerged that can tackle the problem of residue coupling. In recent years, constant-pH molecular dynamics simulations, based on λ-dynamics or Monte Carlo sampling, have become increasingly popular. Rather than keeping the protonation state fixed, titratable sites are allowed to dynamically follow the free energy gradient. Such sampling of (de)protonation events allows one to explicitly capture coupling. We make note of one particular CpHMD approach by Chen and Roux 41 that employs non-equilibrium transformations to generate potential protonation configurations that are accepted or rejected based on a Monte Carlo criterion; this method was assessed for consistency using the Crooks fluctuation theorem. We underscore that our approach, while employing similar transformations, is not a constant-pH method. Instead, we rely on double free energy differences calculated between fixed microstates. Nevertheless, CpHMD is an exceptionally powerful approach for studying pH-dependent phenomena and can readily capture coupling between tittratable sites.