Catechol-O-methyltransferase (COMT) deactivates dopamine and other catecholic substrates via the methylation of a hydroxyl group. The targeted inhibition of COMT can prevent premature metabolism of both endogenous and exogenous ligands; for example, it can prolong the effectiveness of L-DOPA treatments for Parkinson's disease. The inhibitory ability of a suite of dopaminergic derivatives against COMT has been studied using electronic interaction energies between each ligand and the enzymatic active site as well as desolvation energies for each ligand. A crystal structure of the COMT active site in complex with a known COMT inhibitor, BIA 8-176, was isolated from the Protein Data Bank (PDB ID: 2CL5). The positions of a suite of dopaminergic derivatives in this same active site were optimized using M062X/6-31G with three different model chemistries: in vacuo with rigid amino acid side chains, with implicit solvation and rigid amino acid side chains, and with implicit solvation and flexible amino acid side chains. Electronic interaction energies between the ligands and the active site residues were calculated for each model using M06L and MP2 with the 6-311+G* basis set. Ligands with a nitrile substituent were favored over other substituent in vacuo, but this preference was not retained when the same ligands were optimized with implicit solvation; the preference was regained when using implicit solvation and a relaxed active site. Desolvation energies of the ligands were calculated using a series of hydration shells (n=7, 9, 11 and 13) with M062X and the aug-cc-pvdz, cc-pvdz, and cc-pvtz basis sets. Ligands with carboxyl and nitro substituents exhibited the least favorable desolvation energies, whereas ligands with the nitrile substituents exhibited the most favorable desolvation energies.

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The solution flexibility of carbohydrates influences a variety of molecular recognition and regulatory processes. For aldoses and other monosaccharides, this flexibility is dictated by the orientations of the various hydroxyl (OH) groups present, which influences conformer and anomer ratios, interactions among these OH groups, and interactions between them and the surrounding solvent. Depending on the number and position of axial OH groups, a variety of structures can coexist in solutions at equilibrium. In 1950, as part of his pioneering studies on the shape of pyranoside rings, Reeves described the Δ2 effect, the greater destabilization of the pyranose ring conformation when the OH group on carbon 2 (C2 ) is in the axial position. It was later proposed by Angyal that the Δ2 effect could be cancelled by the presence of an axial OH on C3 , termed here the "C3 effect." Employing size-exclusion chromatography, an entropically-controlled separation technique, we have investigated whether or not the C3 and Δ2 effects indeed do compensate for one another with respect to their influence on the solution flexibility of select aldohexoses and aldopentoses. As will be seen, while qualitatively and semiquantitatively this mutual cancellation of effects does occur in aldohexoses, it does not appear to do so in aldopentoses. An explanation for the latter appears to lie in the variety of anomers and conformers present in equilibrium solutions of those aldopentoses studied and in the relative entropic contribution of individual conformers or anomers to the total solution flexibility.

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