5‐fluorouracil dimers in aqueous solution: molecular dynamics in water and continuum solvation *

The interactions established in aqueous solution by a variety of 5‐fluorouracil (FU) dimers in water were examined to elucidate the strength of drug–solvent interactions. Molecular dynamics simulations for clusters made up of the FU dimer alone or embedded in 4, 12, and 100 waters at high temperature, followed by simulated annealing, allowed comparing the dimer structures in the different environments, the solute–solvent radial distribution functions and the cluster energetics. The statistics were consistent with those obtained from a 10 ns MD simulation in the NPT ensemble in 385 waters. Interestingly, the F atom was never preferred to O as H‐bond acceptor either in the dimer or in water. The interactions within the dimers turned out to be remarkably affected by the presence of the solvent: stacked structures, unfavorable in the gas phase, prevailed even in the presence of four water molecules. The presence of real water molecules is thus of paramount importance to stabilize the system, using molecular dynamics or, alternatively, if affordable, the MP2 level. Geometry optimizations of the clusters at the B3LYP/6‐31G* or HF/6‐31G* level, in fact, though starting from a stacked hydrated arrangement of the FU dimer, produced almost exactly the same seashell structure. The polarizable continuum model is convenient to compute the solvation free energy of the dimers and clusters at the HF or MP2 level. Also, the partial charge distribution of the clusters can profitably be used to evaluate the solvent effect in the continuum framework. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem 88: 133–146, 2002