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Maciej Gutowski - One of the best experts on this subject based on the ideXlab platform.
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importance of time scale and local environment in electron driven proton transfer the anion of acetoacetic acid
Journal of the American Chemical Society, 2015Co-Authors: Zibo Goabaone Keolopile, Angela Buonaugurio, Evan Collins, Thomas Lectka, Xinxing Zhang, Kit H Bowen, Maciej Gutowski, Michael AllanAbstract:Anion photoelectron spectroscopy (PES) and electron energy-loss spectroscopy (EELS) probe different regions of the anionic potential energy surface. These complementary techniques provided information about anionic states of acetoacetic acid (AA). Electronic structure calculations facilitated the identification of the most stable Tautomers and conformers for both neutral and anionic AA and determined their relative stabilities and excess electron binding energies. The most stable conformers of the neutral keto and enol Tautomers differ by less than 1 kcal/mol in terms of electronic energies corrected for zero-point vibrations. Thermal effects favor these conformers of the keto tautomer, which do not support an intramolecular hydrogen bond between the keto and the carboxylic groups. The valence anion displays a distinct minimum which results from proton transfer from the carboxylic to the keto group; thus, we name it an ol structure. The minimum is characterized by a short intramolecular hydrogen bond, a s...
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Quantum Mechanical Energy-Based Screening of Combinatorially Generated Library of Tautomers. TauTGen: A Tautomer Generator Program
Journal of Chemical Information and Modeling, 2006Co-Authors: Maciej Haranczyk, Maciej GutowskiAbstract:We describe a procedure of finding low-energy Tautomers of a molecule. The procedure consists of (i) combinatorial generation of a library of Tautomers, (ii) screening based on the results of geometry optimization of initial structures performed at the density functional level of theory, and (iii) final refinement of geometry for the top hits at the second-order Moller−Plesset level of theory followed by single-point energy calculations at the coupled cluster level of theory with single, double, and perturbative triple excitations. The library of initial structures of various Tautomers is generated with TauTGen, a tautomer generator program. The procedure proved to be successful for these molecular systems for which common chemical knowledge had not been sufficient to predict the most stable structures.
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valence and dipole bound anions of the most stable Tautomers of guanine
Journal of the American Chemical Society, 2005Co-Authors: Maciej Haranczyk, Maciej GutowskiAbstract:Anionic states of guanine, which is the only nucleic acid base of which the anions have not yet been studied in either photoelectron spectroscopic (PES) or Rydberg electron transfer (RET) experiments, have been characterized for the four most stable Tautomers of neutral guanine using a broad spectrum of electronic structure methods from the density functional theory, with the B3LYP exchange−correlation functional, to the coupled-cluster method, with single, double, and perturbative triple excitations. Both valence and dipole-bound anionic states were addressed. We identified some of the difficulties facing future PES or RET experiments on the anion of guanine. Even if guanine is successfully transferred to the gas phase without thermal decomposition, it is critical to have the canonical amino−oxo (G) and both amino−hydroxy (GH and GHN7H) Tautomers in the beam, not only the most stable, a noncanonical, amino−oxo tautomer (GN7H), as the latter does not support an adiabatically bound anionic state. We also s...
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Stabilization of very rare Tautomers of uracil by an excess electron.
Physical Chemistry Chemical Physics, 2005Co-Authors: Rafał A. Bachorz, Janusz Rak, Maciej GutowskiAbstract:We characterized valence-type and dipole-bound anionic states of uracil using various electronic structure methods. We found that the most stable anion is related to neither the canonical 2,4-dioxo nor a rare imino-hydroxy tautomer. Instead, it is related to an imino-oxo tautomer, in which the N1H proton is transferred to the C5 atom. This valence anion is characterized by an electron vertical detachment energy (VDE) of 1267 meV and it is adiabatically stable with respect to the canonical neutral by 3.93 kcal mol−1. It is also more stable by 2.32 and 5.10 kcal mol−1 than the dipole-bound and valence anion, respectively, of the canonical tautomer. The VDE values for the former and the latter are 73 and 506 meV, respectively. Another, anionic, low-lying imino-oxo tautomer with a VDE of 2499 meV has a proton transferred from N3H to C5. It is less stable than the neutral canonical tautomer by 1.38 kcal mol−1. The mechanism of formation of anionic Tautomers with the carbon C5 protonated may involve intermolecular proton transfer or dissociative electron attachment to the canonical neutral tautomer followed by a barrier-free attachment of a hydrogen atom to C5. The six-member ring structure of anionic Tautomers with carbon atoms protonated might be unstable upon an excess electron detachment. Indeed, the neutral systems resulting from electron detachment from anionic Tautomers with carbon atoms protonated evolve along barrier-free decomposition pathways to a linear or a bicyclo structure, which might be viewed as lesions to RNA. Within the PCM hydration model, the low-lying valence anions become adiabatically bound with respect to the canonical neutral and the two most stable Tautomers have carbon atoms protonated.
Pavel Hobza - One of the best experts on this subject based on the ideXlab platform.
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na mg2 and zn2 binding to all Tautomers of adenine cytosine and thymine and the eight most stable keto enol Tautomers of guanine a correlated ab initio quantum chemical study
Journal of Physical Chemistry B, 2006Co-Authors: Martin Kabelac, Pavel HobzaAbstract:Interactions of adenine, cytosine, guanine, and thymine with Na+, Mg2+, and Zn2+ cations were studied using an approximate resolution of identity correlated second-order MP2 (RI-MP2) method with the TZVPP ([5s3p2d1f/3s2p1d]) basis set. All existing Tautomers of adenine, cytosine, and thymine and the eight most stable keto/enol Tautomers of guanine were considered. Cations bind mostly in a bidentate manner, and stabilization energies of these complexes are larger than those in the case when cations bind in a unidentate manner. The cation···Y (Y equal to N or O) distances for divalent metals are shorter than those for Na+ and for Zn2+ are mostly shorter than the Mg2+···Y distance. The intermolecular distances between the cation and the base for complexes containing adenine and cytosine are systematically shorter than those for complexes containing guanine and thymine. Only for cytosine the canonical keto/amino tautomer structure with ions represents the global minimum. For guanine, the metalated canonical f...
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correlated ab initio study of nucleic acid bases and their Tautomers in the gas phase in a microhydrated environment and in aqueous solution part 4 uracil and thymine
Physical Chemistry Chemical Physics, 2005Co-Authors: Jaroslav Rejnek, Michal Hanus, Filip Ryjacek, Martin Kabelac, Pavel HobzaAbstract:Altogether 13 keto and enol Tautomers of uracil and 13 keto and enol Tautomers of thymine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in a water environment. Bulk water was described using the thermodynamic integration method, Conductor-like polarizable continuum model (C-PCM, COSMO) and hybrid model (C-PCM + 1–2 explicit water molecules). The structures of various Tautomers were determined at the RI-MP2 level using the TZVPP basis set while relative energies were determined at the CCSD(T) level. The relative free energies at 298 K were based on the relative energies mentioned above and zero-point vibration energies, and temperature dependent enthalpy terms and entropies evaluated at the MP2/6-31G** level. The effect of bulk solvent on the relative stability of uracil and thymine Tautomers was studied using molecular dynamics free energy calculations by means of the thermodynamic integration method and self-consistent reaction field. Despite the completely different nature of these methods they provide comparable solvation free energies. Besides theoretical investigation, experimental detection of uracil and thymine Tautomers was performed by means of steady-state fluorescence. We conclude that it is impossible to utilize the method used by Suwaiyan and Morsy (M. A. Morsy, A. M. Al-Somali and A. Suwaiyan, J. Phys. Chem. B, 1999, 103(50), 11205) for tautomer detection, even if a very sensitive fluorimeter is used. Theoretical relative energies and free energies for isolated uracil and thymine Tautomers support the existence of the canonical form only. The microhydrated environment and bulk solvent stabilize enol forms more than the canonical keto one, but gas phase destabilization of these enol forms is too high. Population of rare enol forms of uracil and thymine in bulk water will thus be very low and canonical structure will also be dominant in this phase.
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correlated ab initio study of nucleic acid bases and their Tautomers in the gas phase in a microhydrated environment and in aqueous solution guanine surprising stabilization of rare Tautomers in aqueous solution
Journal of the American Chemical Society, 2003Co-Authors: Michal Hanus, Filip Ryjacek, Martin Kabelac, Tomas Kubar, Tetyana V Bogdan, Semen A Trygubenko, Pavel HobzaAbstract:Altogether eight keto and enol Tautomers of guanine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in bulk water. The structures of isolated, as well as mono- and dihydrated Tautomers were determined by means of the RI-MP2 method using the extended TZVPP (5s3p2d1f/3s2p1d) basis set. The relative energies of isolated Tautomers included the correction to higher correlation energy terms evaluated at the CCSD(T)/aug-cc-pVDZ level. The relative enthalpies at 0 K and relative free energies at 298 K were based on the above-mentioned relative energies and zero-point vibration energies, temperature-dependent enthalpy terms and entropies evaluated at the MP2/6-31G** level. The keto form having hydrogen atom at N7 is the global minimum while the canonical form having hydrogen atom at N9 represents the first local minimum at all theoretical levels in vacuo and in the presence of 1 and 2 water molecules. All three unusual rare Tautomers having hydrogens at N3 and N7, at N3 and N9, and also at N9 and N7 are systematically considerably less stable and can be hardly detected in the gas phase. The theoretical predictions fully agree with existing theoretical as well as experimental results. The effect of bulk solvent on the relative stability of guanine Tautomers was studied by self-consistent reaction field and molecular dynamics free energy calculations using the thermodynamic integration method. Bulk solvent, surprisingly, strongly favored these three rare Tautomers over all remaining low-energy Tautomers and probably only these forms can exist in water phase. The global minimum (tautomer with hydrogens at N3 and N7) is by 13 kcal/mol more stable than the canonical form (3rd local minimum). Addition of one or two water molecules does not change the relative stability order of isolated guanine Tautomers but the respective trend clearly supports the surprising stabilization of three rare forms.
Claire E. Dickerson - One of the best experts on this subject based on the ideXlab platform.
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Pattern-free generation and quantum mechanical scoring of ring-chain Tautomers
Journal of Computer-Aided Molecular Design, 2020Co-Authors: Daniel S. Levine, Haoyu S. Yu, Mark A Watson, Leif D. Jacobson, Claire E. Dickerson, Arteum D. BochevarovAbstract:In contrast to the computational generation of conventional Tautomers, the analogous operation that would produce ring-chain Tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pK_ a prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated Tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain Tautomers not found using previously published algorithms are successfully located by ours.
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pattern free generation and quantum mechanical scoring of ring chain Tautomers
Journal of Computer-aided Molecular Design, 2020Co-Authors: Daniel S. Levine, Mark A Watson, Leif D. Jacobson, Claire E. Dickerson, Art D BochevarovAbstract:In contrast to the computational generation of conventional Tautomers, the analogous operation that would produce ring-chain Tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pKa prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated Tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain Tautomers not found using previously published algorithms are successfully located by ours.
Daniel S. Levine - One of the best experts on this subject based on the ideXlab platform.
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Pattern-free generation and quantum mechanical scoring of ring-chain Tautomers
Journal of Computer-Aided Molecular Design, 2020Co-Authors: Daniel S. Levine, Haoyu S. Yu, Mark A Watson, Leif D. Jacobson, Claire E. Dickerson, Arteum D. BochevarovAbstract:In contrast to the computational generation of conventional Tautomers, the analogous operation that would produce ring-chain Tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pK_ a prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated Tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain Tautomers not found using previously published algorithms are successfully located by ours.
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pattern free generation and quantum mechanical scoring of ring chain Tautomers
Journal of Computer-aided Molecular Design, 2020Co-Authors: Daniel S. Levine, Mark A Watson, Leif D. Jacobson, Claire E. Dickerson, Art D BochevarovAbstract:In contrast to the computational generation of conventional Tautomers, the analogous operation that would produce ring-chain Tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pKa prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated Tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain Tautomers not found using previously published algorithms are successfully located by ours.
Arteum D. Bochevarov - One of the best experts on this subject based on the ideXlab platform.
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Pattern-free generation and quantum mechanical scoring of ring-chain Tautomers
Journal of Computer-Aided Molecular Design, 2020Co-Authors: Daniel S. Levine, Haoyu S. Yu, Mark A Watson, Leif D. Jacobson, Claire E. Dickerson, Arteum D. BochevarovAbstract:In contrast to the computational generation of conventional Tautomers, the analogous operation that would produce ring-chain Tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pK_ a prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated Tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain Tautomers not found using previously published algorithms are successfully located by ours.
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Generation of Tautomers Using Micro-pKa’s
Journal of Chemical Information and Modeling, 2019Co-Authors: Mark A Watson, Haoyu S. Yu, Arteum D. BochevarovAbstract:Solutions of organic molecules containing one or more heterocycles with conjugated bonds may exist as a mixture of Tautomers, but typically only a few of them are significantly populated even though the potential number grows combinatorially with the number of protonation and deprotonation sites. Generating the most stable Tautomers from a given input structure is an important and challenging task, and numerous algorithms to tackle it have been proposed in the literature. This work describes a novel approach for tautomer prediction that involves the combined use of molecular mechanics, semiempirical quantum chemistry, and density functional theory. The key idea in our method is to identify the protonation and deprotonation sites using estimated micro-pKa’s for every atom in the molecule as well as in its nearest protonated and deprotonated forms. To generate Tautomers in a systematic way with minimal bias, we then consider the full set of Tautomers that arise from the combinatorial distribution of all suc...
