AB-INITIO RELATIVE STABILITY OF A FEW CONFORMERS OF BILIRUBIN IN-VACUO AND IN AQUEOUS-SOLUTION (PCM)

The conformational properties of bilirubin present a considerable inte rest from the medical and biological points of view, because of the to xic pigment peculiar solubility features. Therefore, ab initio geometr y optimizations at the 3-21G/SCF level were carried out on a few model -built structures of bilirubin, after substituting the methyl groups o n the heteroaromatic rings with H atoms. The structures obtained show a varied network of H bonds, ranging from 0 to 6 H bonds for the lowes t-energy conformer in vacuo. This conformer assumes a ''ridge-tile'' s hape previously found in both MM/MD simulations [D. A. Lightner et al. , J. Am. Chem. Sec. 114, 10123 (1992)] and semiempirical calculations [W. H. Shelver et al., Int. J. Quantum Chem. 44, 141 (1992)], but at t he ab initio level, its computed H-bond geometrical parameters are fai rly consistent with the X-ray observed ones. The relative stability of all the structures is compared in vacuo and in aqueous solution using the polarizable continuum model (PCM) of the solvent, whose stabilizi ng effect, however, is not sufficient to fill the large energy gap bet ween the less lipophilic conformers and the most stable one in vacuo, in agreement with previous CD measurements. The energetic cost imposed to the solvent effect by each intramolecular H bond is almost constan t if the other structural features do not change appreciably. The tren d of the purely electrostatic results obtained employing a partial cha rge model of bilirubin is analogous to that produced by its polarized ab initio charge distribution. (C) 1998 John Wiley & Sons, Inc.