The aromatic stacking of hydrocarbons in aqueous solution has been commonly interpreted by the hydrophobic effect that dissolution is opposed by water's preference for interacting with itself relative to interacting with the hydrocarbon, and that water molecules forced to reside near the nonpolar solute have excess energy that is manifested in a higher degree of order than that of bulk water. In contrast, the self-association of heterocycles in aqueous solution has been interpreted to imply that these associations are driven by intrinsic attractions between the heterocyclic rings, namely, the dispersion force and interactions between partial charges on the heterocyclic rings, and a """"""""hidden"""""""" hydrophobic effect. Recently, Gellman et al. have suggested that the aromatic stacking between two heterocyclic moieties, or between a hydrocarbon and a heterocycle, is not a result of the hydrophobic effect, and that the dispersion force is not a dominant promoter of aromatic stacking, based on their NMR study on bis-adenine, bis-phenyl, and bis-naphthyl compounds with a propylene linker. To investigate the aromatic stacking in further detail, molecular dynamics (MD) simulations and potential of mean force (PMF) calculations on the compounds used in Gellman's NMR experiment are proposed, with the aid of the AMBER 4.1 and MidasPlus programs in the Computer Graphics Lab, in hope that molecular dynamics simulations will provide distinctive, dynamic profiles for the stacking behaviors of bis-adenine and bis-naphthyl compounds and insights into understanding the nature of aromatic stacking interaction, and that PMF calculation will provide more conclusive information on the stability of the stacking and nonstacking conformers. In addition, MD simulations and PMF calculations on other compounds (e.g., bis-indole, bis-benzothiophene, and bis-benzofuran analogs) are proposed in an attempt to investigate if the different behaviors of the aromatic stacking of bis-naphthyl and bis-adenine compounds observed in the NMR study stem from the different molecular volumes (6 membered ring versus 5 membered ring) or the different connecting points (meta position versus ortho position) of the naphthyl and adenine groups. Preliminary calculations (MD simulations and PMF calculations) on bis-N-methylindole acetic acid revealed that the non-stacking conformer is more stable than the stacking conformer in aqueous solution, which is consistent with Gellman's suggestion that the aromatic stacking between two heterocyclic moieties or between a hydrocarbon and a heterocycle stems only from electrostatic interaction. The Computer Graphics Lab is essential to check visually the correctness of the numerical calculation. MidasPlus program is routinely used for visual inspection of the trajectories of a MD simulation.
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