Calculating the Absolute Free Energy of Association of Netropsin and DNA

Calculations of the absolute free energy of association of netropsin to the Dickerson dodecamer [d(CGCGAATTGCGC)] 2 have been carried out, using the double annihilation method and electrostatic decoupling and an all-atom model of DNA and netropsin in a periodic box of water. The calculated free energy of association is −10.3 kcal/mol, in good agreement with the low salt value of −11.5 kcal/mol for a related sequence [d(GCGAATTCGC)] 2 1a and −10.2 kcal/mol for [d(CGCAAATTGGC) 2 ]. 1b Separate calculation of the electrostatic and van der Waals free energies leads to the conclusion that the predominant contribution to association is the van der Waals energy, despite the +2 charge of netropsin and the polyanionic nature of the DNA. This is because the electrostatic free energy is almost identical for removing the charges of netropsin in water and when bound to DNA. Our calculations show that 14 molecules diffuse into the GAATTC binding site of netropsin, consistent with our determination of the number of water molecules that are present at that site in the crystal structure of [d(CGCAAATTGGC) 2 ]. 2a,b