THE OSMOTIC SENSITIVITY OF NETROPSIN ANALOG BINDING TO DNA

The binding of a netropsin analogue to random sequence DNA monitored b y CD, is seen dependent on the concentration of neutral solutes. The b inding free energy decreases linearly with solute osmolal concentratio n and the magnitude of the effect is insensitive to the chemical ident ity of the solute for betaine, sorbitol, and triethylene glycol. These solutes appear to modulate binding through their effect on water acti vity and changes in the hydration of the drug and DNA in the complex r eaction, not through a direct interaction with the reactants or the pr oduct. The dependence of binding constant on solute concentration can be interpreted as an additional binding of some 50-60 extra solute exc luding water molecules by the complex. A water sensitivity of drug bin ding is further seen from the dependence of binding constants on the t ype of anion in solution. Anions in the Hofmeister series strongly aff ect bulk water free energies and entropies. The differences in netrops in analogue binding to DNA with Cl-, F-, and ClO4- are consistent with the effect observed with neutral solutes. The ability to measure chan ges in water binding associated with a specific DNA interaction is a f irst step toward correlating changes in hydration with the strength an d specificity of binding. (C) 1995 John Wiley & Sons, Inc.