The geometry of the ground state and the first singlet excite state of adenine and 2-aminopurine was calculated with three different quantum chemical methods: AM1, CIS/6-31G, and CASSCF/6-31G. Three possible deactivation mechanisms or reactions of excited molecule were considered: the pseudo Jahn-Teller distortion, excited-state tautomerism, and formation of so-called twisted intramolecular charge transfer (TICT) states. Different mechanisms for the nonradiative decay are operative for the two isomers. The geometrically relaxed excited state of adenine has n f π* character, while it has π f π* character for 2-aminopurine. The state crossing that occurs during the excited-state relaxation of adenine opens up an effective nonradiative deactivation channel not present for 2-aminopurine. Tautomerism in the excited state might explain the difference in luminescence quantum yield upon DNA binding for 2-aminopurine. The excited state of the 7H tautomer of adenine undergoes a large geometry change during the relaxation, and the final geometry of the n f π* state resembles a TICT state, but with only little charge transfer.

The absorption spectra and transition moment directions of the four DNA bases and uracil were calculated, utilizing the semiempirical INDO/S-CI method and the ab initio CIS/6-31G* method. A linear scaling of the CIS/6-31G* transition energies was necessary to get good agreement with the observed energies. CASPT2 π → π* transition energies and polarizations of adenine were also calculated. Fully MP2/6-31G*-optimized geometries were used in the calculations of the electronic spectra. The effect of possible tautomerism was investigated by calculation of the spectrum of several tautomers of guanine and cytosine. Specific and nonspecific solvent effects were considered in the calculations. Nonspecific solvent effects were modeled by a continuum model. Specific solvent interactions were modeled by inclusion of one water molecule in “supermolecule” calculations of the geometry and the spectrum of cytosine and guanine. Experimental transition energies were reproduced with an average error of less than 0.3 eV, and in most cases even better. Transition moment directions were calculated in good agreement with observations and other theoretical results in most cases. In some cases directions do not agree with observations. In these cases we have shown that the observed directions might be affected by the presence of more than one tautomeric form or by solvent or crystal effects. We propose a new interpretation of the π → π* absorption spectrum of cytosine and guanine due to solvent effects and tautomerism. A simple model, based on symmetry and geometry arguments, was used to rationalize the computed transition moment directions.

In drug design, it is crucial to have reliable information on how a chemical entity behaves in the presence of metabolizing enzymes. This requires substantial experimental efforts. Consequently, being able to predict the likely site/s of metabolism in any compound, synthesized or virtual, would be highly beneficial and time efficient. In this work, six different methodologies for predictions of the site of metabolism (SOM) have been compared and validated using structurally diverse data sets of drug-like molecules with well-established metabolic pattern in CYP3A4, CYP2C9, or both. Three of the methods predict the SOM based on the ligand's chemical structure, two additional methods use structural information of the enzymes, and the sixth method combines structure and ligand similarity and reactivity. The SOM is correctly predicted in 50 to 90% of the cases, depending on method and enzyme, which is an encouraging rate. We also discuss the underlying mechanisms of cytochrome P450 metabolism in the light of the results from this comparison.

The connections between site structure, electronic structure and spectra, and electron-transfer properties of type 1 or blue copper proteins are investigated. The theoretical model includes the nearest neighbors of the Cu ion and the residues to which these neighbors are attached. The electronic structure is calculated using an extended CNDO/S method adapted to spin doublet states. The calculated spectra agree reasonably well with the experimental ones as well as with the calculations of Solomon et al. The strong absorption at about 16 000 cm-' is due to a n -n* transition, where the n and n* orbitals are extended in the trigonal plane with Cu 3&, S 3pn, and, to a lesser extent, N 2p0 character. Strong absorption at other energies is due to ligand field transitions which borrow intensity from the n -n* transition because of symmetry lowering from C2". Comments, based on calculations, are offered on copper-zinc superoxide dismutase mutants, whose spectral properties to some extent resemble those of the blue proteins.