A correlated ab initio quantum chemical study of the interaction of the Na+, Mg2+, Ca2+ and Zn2+ ions with the tautomers of cytosine in the presence of polar solvent.

The interactions of the metal ions Na(+), Mg(2+), Ca(2+) and Zn(2+) with cytosine have been investigated with inclusion of solvent effects. Computations have been performed at the density functional and Møller-Plesset levels of theory within the IEFPCM solvent model. It has been found that the inclusion of the solvent environment is essential for giving more biologically realistic results. Earlier gas-phase findings of the stabilisation of rare tautomeric forms by the metal ions have been reproduced, with the presence of the solvent further affecting the relative stabilities.

Studies of the ground and excited-state surfaces of the retinal chromophore using CAM-B3LYP.

The isomerization of the 11-cis isomer (PSB11) of the retinal chromophore to its all-trans isomer (PSBT) is examined. Optimized structures on both the ground state and the excited state are calculated, and the dependence on torsional angles in the carbon chain is investigated. Time-dependent density functional theory is used to produce excitation energies and the excited-state surface. To avoid problems with the description of excited states that can arise with standard DFT methods, the CAM-B3LYP functional was used. Comparing CAM-B3LYP with B3LYP results indicates that the former is significantly more accurate, as a consequence of which detailed cross sections of the retinal excited-state surface are obtained.

Calculation of a Complete Enzymic Reaction Surface: Reaction and Activation Free Energies for Hydride-Ion Transfer in Dihydrofolate Reductase.

We present a two-dimensional grid method for the calculation of complete free-energy surfaces for enzyme reactions using a hybrid quantum mechanical/molecular mechanical (QM/MM) potential within the semiempirical (PM3) QM approximation. This implementation is novel in that parallel processing with multiple trajectories (replica-exchange molecular dynamics simulations) is used to sample configuration space. The free energies at each grid point are computed using the thermodynamic integration formalism. From the free-energy surface, the minimum free-energy pathway for the reaction can be defined, and the computed activation and reaction energies can be compared with experimental values. We illustrate its use in a study of the hydride-transfer step in the reduction of dihydrofolate to tetrahydrofolate catalyzed by Escherichia coli dihydrofolate reductase with bound nicotinamide adenine dinucleotide phosphate cofactor. We investigated the effects of changing the QM region, ionization state of the conserved active-site Asp27 residue, and polarization contributions to the activation and reaction free energy. The results clearly show the necessity for including the complete substrate and cofactor molecules in the QM region, and the importance of the overall protein (MM) electrostatic environment in determining the free energy of the transition state (TS) and products relative to reactants. For the model with ionized Asp27, its inclusion in the QM region is essential. We found that the reported [Garcia-Viloca, M.; Truhlar, D. G.; Gao, J. J. Mol. Biol. 2003, 327, 549] stabilization of the TS due to polarization is an artifact that can be attributed to truncation of the electrostatic interactions between the QM and MM atoms. For neutral (protonated) Asp27, our calculated reaction free energy of -4 ± 2 kcal/mol agrees well with the experimental value of -4.4 kcal/mol, although the corresponding activation free-energy estimate is still high at 21 ± 2 kcal/mol compared with the experimental value of 13.4 kcal/mol. The results are less supportive of the ionized Asp27 model, which gives rise to a much higher activation barrier and favors the reverse reaction.