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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, 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-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.
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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...
Maciej Gutowski - One of the best experts on this subject based on the ideXlab platform.
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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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interaction with glycine increases stability of a mutagenic Tautomer of uracil a density functional theory study
Journal of the American Chemical Society, 2005Co-Authors: Iwona Dabkowska, Maciej Gutowski, Janusz RakAbstract:The most stable structures for complexes of minor Tautomers of uracil (U) with glycine (G) were characterized at the density functional B3LYP/6-31++G** level of theory. These are cyclic structures stabilized by two hydrogen bonds. The relative stability of isolated Tautomers of uracil was rationalized by using thermodynamic and structural arguments. The stabilization energies for complexes between Tautomers of U and G result from interplay between stabilizing two-body interaction energies and destabilizing one-body terms. The latter are related to the energies of: (i) Tautomerization of the unperturbed moieties and (ii) distortions of the Tautomers in the complex. The two-body term is related to the interaction energy between distorted Tautomers. The two-body interaction energy term correlates with perturbations of length of the Y-H proton-donor bonds as well as with deprotonation enthalpies and proton affinities of the appropriate monomers sites. It was demonstrated that the relative instability of rare Tautomers of uracil is diminished due to their interactions with glycine. In particular, the instability of the third most stable Tautomer is decreased from 11.9 kcal/mol for an isolated uracil to 6.7 kcal/mol in a complex with the zwitterionic Tautomer of glycine. A decrease of instability by 5.2 kcal/mol in the free enthalpy scalemore » could result in an increase of concentration of this Tautomer by almost five orders of magnitude. Such a concentration falls in the mutationally significant range. The increased stability of the third Tautomer of uracil, and probably thymine, can be relevant for point mutations because its proton donor and acceptor sites are complementary with those of guanine rather than these of adenine.« less
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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.
Mark A Watson - 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, 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-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.
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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...
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, 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-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, 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-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.
