Molecular recognition between peptide blockers and ionic channels is a complex process that involves many effects. To determine if the short-range charge transfer effects play a significant role in this interaction, a chemical reactivity analysis of charybdotoxin (ChTX) and six of its mutants was carried out using global and local reactivity indices. The results show that global softness correlates with the affinity of ChTX, and its mutants to the channel indicating that soft–soft interactions play a role in the recognition process between ChTX and a potassium channel. The analysis of the local reactivity indicates that the toxin as a whole can be seen as a complex polydentate ligand with several places to coordinate with the external vestibule of the pore of the potassium channels. The successful treatment of point mutations supports the idea of using this tool in the study of chemical reactivity in proteins, in a similar way as substituent effects in organic chemistry. © 2012 Wiley Periodicals, Inc.