The results of a comprehensive study on the double-proton transfer in Adenine-Thymine (AT) and Guanine-Cytosine (GC) base pairs at room temperature in gas phase and with the inclusion of environmental effects are obtained. The double-proton-transfer process has been investigated in the AT and GC base pairs at the B3LYP/6-31G(d) and MP2/6-31G(d) levels of theory. It has been predicted that the hydrogen-bonded bases possess nonplanar geometries due to sp3 hybridization of nitrogen atoms and because of the soft intermolecular vibrations in the molecular complexes. An analysis of the energetic parameters of the local minima suggests that rare AT base pair conformation is not populated due to the shallowness of this minimum, which completely disappears from the Gibbs free energy surface. The stabilization of canonic or rare forms of the DNA bases by water molecules and metal cations has been predicted by calculating the optimal configuration of charges (using differential product/transition state stabilization approach) followed by calculations of the interactions between the base pair and a water/sodium cation.
The results of an ab initio post-Hartree-Fock study of the protonation of all nucleic acid bases are reported. Rare tautomers of guanine and cytosine, which coexist in the gas phase with the major forms, were also included in the study. The geometries of the local minima and transition states were optimized without symmetry restrictions by the gradient procedure at the HF and MP2 levels of theory and were verified by energy secondderivative calculations. The standard 6-31+G(d,p) basis set was used. The single-point calculations have been performed at the MP4(SDTQ)/6-31+G(d,p)//MP2/6-31+G(d,p) and MP2/6-311++G(d,p)//MP2/6-31+G-(d,p) approximations. The relative stabilities of the different protonated forms of all nucleic acid bases have been reported. The values of proton affinities (PA) for each base including contributions of rare tautomers and different protonated forms for guanine and cytosine have been calculated. We have shown that the calculated values of proton affinities are very close to the experimental data, and the differences are in the range of 0.0-2.1%. We have concluded that all levels of the Mo ¨ller-Plesset theory considered in the study are able to describe the PA values of nucleic acid bases with experimental accuracy. The study has shown that the rare tautomers make up a significant portion of the gas-phase equilibrium mixture. Yet, the values of the proton affinities change only slightly with the inclusion of rare forms into the calculations.
High-level quantum-chemical and quantum-dynamics calculations are reported on the tautomerization equilibria and rate constants of isolated and monohydrated cytosine and guanine molecules. The results are used to estimate the fraction of the bases present in the cell during DNA synthesis as the unwanted tautomers that forms irregular base pairs, thus giving rise to a spontaneous GC → AT point mutation. A comparison of the estimated mutation frequencies with the observed frequency in E. coli is used to analyze two proposed mechanisms, differing in the degree of equilibration reached in the tautomerization reaction.It was found that the fraction of the rare tautomer in monohydrated complex of cytosine as well as guanine significantly exceed the amount responsible for the observed values of the GC → AT mutations. In the absence of water the equilibrium concentration of tautomeric forms is relatively large, but the barrier to their formation is high. It is possible that the mechanism in which a high tautomerization barrier keeps the tautomeric transformation far from a state of equilibrium is more likely than a mechanism in which water and/or polymerases produce a low equilibrium concentration of the tautomeric forms.
The mechanism of the double-proton transfer in the formamide−formamidine dimer, which is the simplest model resembling the hydrogen bonding pattern in the adenine−thymine base pair, has been studied by means of ab initio post-Hartree−Fock calculations. The optimizations of all local minima and transition states were performed for both the gas phase and water solution using density functional theory (B3LYP), second-order Møller−Plesset theory, and the quadratic configuration interaction method using various basis sets. Additional optimizations of the structures with explicitly included water molecules were performed at the B3LYP level of theory. The two-dimensional adiabatic surfaces have been calculated for the process of double-proton transfer in both the gas phase and a polar surrounding. The results of the calculations indicate that the gas-phase double-proton transfer possesses a concerted and asynchronous mechanism. However, due to the stabilization of the zwitterionic structure by a polar medium, the latter becomes a local minimum in the water solution where the reaction proceeds through a stepwise mechanism.
With de novo rational drug design, scientists can rapidly generate a very large number of potentially biologically active probes. However, many of them may be synthetically infeasible and, therefore, of limited value to drug developers. On the other hand, most of the tools for synthetic accessibility evaluation are very slow and can process only a few molecules per minute. In this study, we present two approaches to quickly predict the synthetic accessibility of chemical compounds by utilizing support vector machines operating on molecular descriptors. The first approach, RSsvm, is designed to identify the compounds that can be synthesized using a specific set of reactions and starting materials and builds its model by training on the compounds identified as synthetically accessible or not by retrosynthetic analysis. The second approach, DRsvm, is designed to provide a more general assessment of synthetic accessibility that is not tied to any set of reactions or starting materials. The training set compounds for this approach are selected from a diverse library based on the number of other similar compounds within the same library. Both approaches have been shown to perform very well in their corresponding areas of applicability with the RSsvm achieving receiver operator characteristic score of 0.952 in cross-validation experiments and the DRsvm achieving a score of 0.888 on an independent set of compounds. Our implementations can successfully process thousands of compounds per minute.
High‐level quantum‐chemical and quantum‐dynamics calculations are reported on the tautomerization equilibrium and rate constants of guanine and its complexes with one and two water molecules. The results are used to estimate the fraction of guanine present in the cell during DNA synthesis as the unwanted tautomer that forms an irregular base pair with thymine, thus giving rise to a spontaneous GC → AT point mutation. A comparison of the estimated mutation frequency with the observed frequency in Escherichia coli is used to analyze two proposed mechanisms, differing in the extent of equilibration reached in the tautomerization reaction. In the absence of water, the equilibrium concentration of tautomeric forms is relatively large, but the barrier to their formation is high. If water is present, tautomeric forms are less favored, but water molecules may serve as efficient proton conduits causing rapid tautomerization. It is tentatively concluded that the mechanism in which a high tautomerization barrier keeps the tautomeric transformation far from a state of equilibrium is more likely than a mechanism in which water and/or polymerases produce a low equilibrium concentration of the tautomeric forms. © 2002 Wiley Periodicals, Inc. Biopoly (Nucleic Acid Sci) 61: 77–83, 2002; DOI 10.1002/bip.10062
The knowledge of a pharmacophore, or the 3D arrangement of features in the biologically active molecule that is responsible for its pharmacological activity, can help in the search and design of a new or better drug acting upon the same or related target. In this paper we describe two new algorithms based on the frequent clique detection in the molecular graphs. The first algorithm mines all frequent cliques that are present in at least one of the conformers of each (or a portion of all) molecules. The second algorithm exploits the similarities among the different conformers of the same molecule and achieves an order of magnitude performance speedup compared to the first algorithm. Both algorithms are guaranteed to find all common pharmacophores in the dataset, which is confirmed by the validation on the set of molecules for which pharmacophores have been determined experimentally. In addition, these algorithms are able to scale to datasets with arbitrarily large number of conformers per molecule and identify multiple ligand binding modes or multiple binding sites of the target.
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