One of the clinically most important classes of DNA/RNA reactive agents are the intercalating drugs, such as proflavine and adryamicin. As an example, we have considered the hydrated complex of N,N--dimethylproflavine and an RNA duplex in the crystal phase. Structural information is provided exclusively by x-ray diffraction, which encounters two main difficulties:\ 1) the positions of the hydrogen atoms are missing; 2) the presence of water molecules is elusive, partly due to structural and dynamical disorder. We have carried out a full structural optimization from first principles, using density functional theory-based calculations. The system contains 244 atoms (134 heavy atoms and 110 hydrogens). The measured structural parameters are well reproduced. Our calculations establish the interaction between the two Watson--Crick base pairs of the RNA fragment as well as the complex H-bond network of the 16 water molecules detected in the crystal unit cell, and provide suggestions on the mode of action of the drug.
By: Paolo Carloni and Wanda Andreoni
Published in: RZ2758 in 1995
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