An artificial histone is synthesized that functions as a DNA-protein digital switch, where DNA binding is all or none, controlled by a sharp threshold of protein charge. A non-DNA-binding protein, glucose oxidase (GOx), was chemically modified by attaching an increasing number of triethylenetetramine (TETA) side chains to its glutamate/aspartate groups to obtain a small library of covalently modified GOx(n) derivatives. The parameter n denotes the net charge on the protein at pH 7, which was increased from -62 (pristine GOx) to +75 by attaching an increasing number of TETA residues to the protein. All GOx(n) derivatives retained their secondary structure to a good extent, as monitored by UV circular dichroism (CD) spectroscopy, and they also retained oxidase activities to a significant extent. The interaction of the GOx(n) with calf thymus DNA was examined by isothermal titration calorimetry (ITC). Pristine GOx of -62 charge at pH 7 in 10 mM Tris-HCl and 50 mM NaCl buffer had no affinity for the negatively charged DNA helix, and GOx(n) with n < +30 had no affinity for DNA either. However, binding has been turned on abruptly when n >= +30 with binding constants (K-b) ranging from (1.5 +/- 0.7) x 10(7) to (7.3 +/- 2.8) x 10(7) M-1 for n values of +30 and +75, respectively, and this type of "all-or-none" binding based on protein charge is intriguing. Furthermore, thermodynamic analysis of the titration data revealed that binding is entirely entropy-driven with Delta S ranging from 0.09 +/- 0.007 to 0.19 +/- 0.008 kcal/mol K with enthalpic penalties of 17.0 +/- 2.3 and 46.1 +/- 2.1 kcal/mol, respectively. The binding had intrinsic propensities (Delta G) ranging from -9.8 +/- 0.14 to-10.7 +/- 0.25 kcal/mol, independent of n. DNA binding distorted protein-DNA secondary structure, as evidenced by CD spectroscopy, but oxidase activity of GOx(n)/DNA complexes has been unaffected. This is the very first example of an artificial histone (GOx(n)) where the protein charge functioned as a DNA-binding switch; protein charge is in turn under complete chemical control while preserving the biological activity of the protein. The new insight gained here could be useful in the design of novel "on-off" protein switches.