Electrostatic factors in DNA intercalation

The factors that determine the binding of a chromophore between the base pa irs in DNA intercalation complexes are dissected The electrostatic potentia l in the intercalation plane is calculated using an accurate ab initio base d distributed multipole electrostatic model for a range of intercalation si res, involving different sequences of base pairs and relative rn isl angles . There will be a significant electrostatic contribution to the binding ene rgy for chromophores with a predominantly positive electrostatic potential, but this varies significantly with sequence, and somewhat with twist angle . The usefulness of these potential maps for understanding the binding of i ntercalators is explored by calculating the electrostatic Binding energy fo r 9-aminoacridine, ethidium, and daunomycin in a variety of model binding s ites. The electrostatic forces play a major role in the positioning of an i ntercalating 9-aminoacridine and a significant stabilizing rob in the bindi ng of ethidium in its sterically constrained position, but the intercalatio n of daunomycin is determined by the side-chain binding. Sequence preferenc es are likely to be determined by a complex and subtle mixture of effects, with electrostatics being just one component. The electrostatic binding ene rgy is also unlikely to be a major determinant of the twist angle, as its v ariation with angle is modest for most intercalation sires. Overall the ele ctrostatic potential maps give guidance on how positively charged chromopho res can be chemically adapted by heteroatomic substitution to optimise thei r binding. (C) 2000 John Wiley & Sons, Inc.