Atomic substitution is a promising approach for controlling structures and properties for developing clusters with desired responses. Although many possible coordination candidates could be deduced for substitution, not all can be prepared. Therefore, predicting the correlation between structures and physical properties is important prior to synthesis. In this study, regarding Keggin-type polyoxometalates (POMs) as a model cluster, the dominant factors affecting the protonation were investigated by atomic substitutions and geometry changes. The valence of Keggin-type POMs and the constituent elements of the cluster shell structure affect the charge and potential distribution, which change the protonation sites. Furthermore, the valence of Keggin-type POMs and the bond length between the core and shell structure determine the protonation energy. These factors also affect the HOMO-LUMO gap, which governs photochemical and redox reactions. These governing factors derived from actual parameters of the α-isomer of Keggin-type POMs enabled us to deduce the protonation energy of the β-isomer, which is more difficult to prepare and isolate than the α-isomer.