Entropy Balance in the Intercalation Process of an Anti-Cancer Drug Daunomycin

The interplay of entropy components in a molecular recognition process is complex but intriguing. In this study, we probed into the origin of this interplay among the drug, DNA, and water entropy in the intercalation process (free -> minor groove-bound -> intercalation) of an anticancer drug daunomycin, resulting in small entropy difference (+1.1 kcal/mol) in excellent agreement with experiment (-1.1 kcal/mol). Using extensive all-atom simulations (>0.6 mu s in total), followed by quasi- harmonic entropy calculation (with prior permutation reduction for water) and rigorous anharmonic and mutual information corrections, this study captures differing trends of drug and DNA entropy in different bound states. Overall water entropy change is positive although somewhat controlled due to the formation of bigger solvation layer in the bound states. This study encompasses for the first time all of the different entropy contributions including water in a biomolecular recognition process depicting entropy compensation similar to the ubiquitous enthalpy/entropy compensation prevalent in chemistry.