Complexation of positively charged sites in a protein with the negative DNA phosphate groups shields the phosphate charges. This diminishes interstrand electrostatic repulsions, which stabilizes the duplex. When phosphate shielding is present in one DNA strand only, the conformation of this strand changes due to a decrease of intrastrand phosphate-phosphate repulsions. This destabilizes the duplex since then the strands differ in conformation. A thermodynamic model is formulated to describe this stabilization/destabilization effect in terms of changed enthalpies and entropies of hybridization. It is found that protein complexation with one DNA strand can indeed lower the TM value of a duplex. The model is applied to the action of helicases (replication), RNA polymerases (transcription), and restriction endonucleases. Mechanisms with unilateral charge shielding are proposed for their duplex-destabilizing properties.