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Handley C.M.,Manchester Interdisciplinary Biocentre MIB | Handley C.M.,University of Manchester | Handley C.M.,University of Warwick | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | And 2 more authors.
Journal of Physical Chemistry A | Year: 2010

Molecular mechanics is the tool of choice for the modeling of systems that are so large or complex that it is impractical or impossible to model them, by ab initio methods. For this reason there is a need for accurate potentials that are able to quickly reproduce ab initio quality results at the fraction of the cost. The interactions within force fields are represented by a number of functions. Some interactions are well understood and can be represented by simple mathematical functions while others are not so well understood and their functional form is represented in a simplistic manner or not even known. In the last 20 years there have been the first examples of a new design ethic, where novel and contemporary methods using machine learning, in particular, artificial neural networks, have been used to find the nature of the underlying functions of a force field. Here we appraise what has been achieved over this time and what requires further improvements, while offering some insight and guidance for the development of future force fields. © 2010 American Chemical Society.

Harding A.P.,Manchester Interdisciplinary Biocentre MIB | Harding A.P.,University of Manchester | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester
Physical Chemistry Chemical Physics | Year: 2011

The prediction of pKa continues to attract much attention with ongoing investigations into new ways to predict pKa accurately, where predicted pKa values deviate less than 0.50 log units from experiment. We show that a single descriptor, i.e. an ab initio bond length, can predict pKa. The emphasis was placed on model simplicity and a demonstration that more accurate predictions emerge from single-bond-length models. A data set of 171 phenols was studied. The carbon-oxygen bond length, connecting the OH to the phenyl ring, consistently provided accurate predictions. The pKa of meta- and para-substituted phenols is predicted here by a single-bond-length model within 0.50 log units. However, accurate prediction of the pKa of ortho-substituted phenols necessitated their splitting into groups called high-correlation subsets in which the pKa of the compounds strongly correlated with a single bond-length. The highly compound-specific single-bond-length models produced better predictions than models constructed with more compounds and more bond lengths. Outliers were easily identified using single-bond-length models and in most cases we were able to determine the reason for the outlier discrepancy. Furthermore, the single-bond-length models showed better cross-validation statistics than the PLS models constructed using more than one bond length. For all of the single-bond-length models, RMSEE was less than 0.50. For the majority of the models, RMSEP was less than 0.50. The results support the use of multiple high-correlation subsets and a single bond-length to predict pK a. Six one-term linear equations are listed as a starting point for the construction of a more comprehensive list covering a larger variety of compound classes. © the Owner Societies.

Azofra L.M.,Institute Quimica Medica | Alkorta I.,Institute Quimica Medica | Elguero J.,Institute Quimica Medica | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester
Carbohydrate Research | Year: 2012

The potential energy surfaces for the different configurations of the d-erythrose and d-threose (open-chain, α- and β-furanoses) have been studied in order to find the most stable structures in the gas phase. For that purpose, a large number of initial structures were explored at B3LYP/6-31G(d) level. All the minima obtained at this level were compared and duplicates removed. A further reoptimization of the remaining structures was carried out at B3LYP/6-311++G(d,p) level. We characterized 174 and 170 minima for the open-chain structures of d-erythrose and d-threose, respectively, with relative energies that range over an interval of just over 50 kJ/mol. In the case of the furanose configurations, the number of minima is smaller by approximately one to two dozen. G3B3 calculations on the most stable minima indicate that the α-furanose configuration is the most stable for both d-erythrose and d-threose. The intramolecular interactions of the minima have been analyzed with the Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) methodologies. Hydrogen bonds were classified as 1-2, 1-3 or 1-4, based on the number of C-C bonds (1, 2 and 3, respectively) that separate the two moieties participating in the hydrogen bond. In general, the AIM and NBO methodologies agree in the designation of the moieties involved in hydrogen bond interactions, except in a few cases associated to 1-2 contact which have small OH⋯O angles. © 2012 Elsevier Ltd. All rights reserved.

Harding A.P.,Manchester Interdisciplinary Biocentre MIB | Harding A.P.,University of Manchester | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester
Physical Chemistry Chemical Physics | Year: 2011

The prediction of pKa from a single ab initio bond length has been extended to provide equations for benzoic acids and anilines. The HF/6-31G(d) level of theory is used for all geometry optimisations. Similarly to phenols (Part 2 of this series of publications), the meta-/para-substituted benzoic acids can be predicted from a single model constructed from one bond length. This model had an impressive RMSEP of 0.13 pKa units. The prediction of ortho-substituted benzoic acids required the identification of high-correlation subsets, where the compounds in the same subset have at least one of the same (e.g. halogens, hydroxy) ortho substituent. Two pKa equations are provided for o-halogen benzoic acids and o-hydroxybenzoic acids, where the RMSEP values are 0.19 and 0.15 pKa units, respectively. Interestingly, the bond length that provided the best model differed between these two high-correlation subsets. This demonstrates the importance of investigating the most predictive bond length, which is not necessarily the bond involving the acid hydrogen. Three high-correlation subsets were identified for the ortho-substituted anilines. These were o-halogen, o-nitro and o-alkyl-substituted aniline high-correlation subsets, where the RMSEP ranged from 0.23 to 0.44 pKa units. The RMSEP for the meta-/para-substituted aniline model was 0.54 pKa units. This value exceeded our threshold of 0.50 pKa units and was higher than both the m-/p-benzoic acids in this work and the m-/p-phenols (RMSEP = 0.43) of Part 2. Constructing two separate models for the meta- and para- substituted anilines, where RMSEP values of 0.63 and 0.33 pKa units were obtained respectively, revealed it was the meta-substituted anilines that caused the large RMSEP value. For unknown reasons the RMSEP value increased with the addition of a further twenty meta-substituted anilines to this model. The C-N bond always produced the best correlations with pKa for all the high-correlation subsets. A higher level of theory and an ammonia probe improved the statistics only marginally for the hydroxybenzoic acid high-correlation subsets. © the Owner Societies.

Alkorta I.,Institute Quimica Medica | Elguero J.,Institute Quimica Medica | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB
Journal of Physical Organic Chemistry | Year: 2011

The effect of complexation with Lewis acids on the tautomeric equilibrium of a derivative of pyridoxal has been explored using density functional theory. Three complexation sites (pyridine nitrogen, aromatic ring, and carbonyl group) have been considered. The tautomeric equilibrium can be modulated with the formation of complexes at the different sites. The changes observed in the geometric, energetic and electronic properties of the tautomers and transition states have been analyzed. Relationships have been found between those parameters, including a relationship between energetic and geometric parameters in agreement with the Hammond postulate. Copyright © 2010 John Wiley & Sons, Ltd.

Alkorta I.,Polytechnic University of Valencia | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB
Carbohydrate Research | Year: 2011

For the first time the mutarotation mechanism of furanose rings has been investigated, with and without solvent. The transformations from open-chain furanose to d-erythrose and d-threose have been studied at B3LYP/6-311++G(d,p) and G3MP2B3 levels, in vacuum and in solution through continuum solvation models. We studied the catalytic influence of one, two or three water molecules, as well as simplified models of carbohydrates, that is, methanol and 1,2-ethanediol. Water molecules significantly reduce the energy barrier of the hemiacetal formation occurring between the open-chain and furanose configurations. The energy barrier is optimally reduced by two water molecules. Methanol yields a smaller transition state barrier than the one obtained with a single water molecule. In contrast, 1,2-ethanediol does not provide a lower transition state compared to the barrier in the presence of two water molecules. © 2011 Elsevier Ltd. All rights reserved.

Garcia-Revilla M.,University of Oviedo | Francisco E.,University of Oviedo | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester | Pendas A.M.,University of Oviedo
ChemPhysChem | Year: 2013

A novel solution to the problem of assigning a molecular graph to a collection of nuclei (i.e. how to draw a molecular structure) is presented. Molecules are universally understood as a set of nuclei linked by bonds, but establishing which nuclei are bonded and which are not is still an empirical matter. Our approach borrows techniques from quantum chemical topology, which showed for the first time the construction of chemical graphs from wave functions, shifting the focus on energetics. This new focus resolves issues surrounding previous topological analyses, in which domain-averaged exchange-correlation energies (Vxc), quantities defined in real space between each possible atom pair, hold the key. Exponential decay of V xc in non-metallic systems as the intercenter distance increases guarantees a well-defined hierarchy for all possible Vxc values in a molecule. Herein, we show that extracting the set of atom pairs that display the largest Vxc values in the hierarchy is equivalent to retrieving the molecular graph itself. Notably, domain-averaged exchange-correlation energies are transferable, and they can be used to calculate bond strengths. Fine-grained details resulted to be related to simple stereoelectronic effects. These ideas are demonstrated in a set of simple pilot molecules. Draw me a molecule: The spatial distribution of atoms in a molecule in the form of chemical graphs is obtained for a set of molecules, using their corresponding domain-averaged exchange-correlation energies (Vxc). Conveniently, such energies are transferable (for 1, n interactions in saturated linear hydrocarbons) and can provide an accurate estimation of the covalent-like contribution between pairs of given interacting topological atoms A and B. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mills M.J.L.,Manchester Interdisciplinary Biocentre MIB | Mills M.J.L.,University of Manchester | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester
Computational and Theoretical Chemistry | Year: 2011

We describe an intramolecularly polarisable multipolar electrostatic potential model for ethanol, which acts as a pilot molecule for this proof-of-concept study. We define atoms via the partitioning prescribed by quantum chemical topology (QCT). A machine learning method called Kriging is employed to capture the way atomic multipole moments vary upon conformational change. The multipole moments predicted by the Kriging models are used in the calculation of atom-atom electrostatic interaction energies. Charge transfer is treated in the same way as dipolar polarisation and the polarisation of higher rank multipole moments. This method enables the development of a new and more accurate force field. © 2011 Elsevier B.V.

Garcia-Revilla M.,University of Oviedo | Popelier P.L.A.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester | Francisco E.,University of Oviedo | Martin Pendas A.,University of Oviedo
Journal of Chemical Theory and Computation | Year: 2011

We analyze the behavior of the profiles of delocalization indices (DIs) between relevant pairs of atoms along reaction coordinates for a set of model chemical processes. A relationship between the topology of the DI and the nature of the underlying chemical change is reported. As shown, exponential shapes correspond to the traditional category of repulsive/nonbonded interactions, while sigmoidal profiles signal the formation/breaking of chemical links. © 2011 American Chemical Society.

Mills M.J.L.,Manchester Interdisciplinary Biocentre MIB | Popelier P.L.A.,University of Manchester
Theoretical Chemistry Accounts | Year: 2012

We present a polarisable multipolar interatomic electrostatic potential energy function for force fields and describe its application to the pilot molecule MeNH-Ala-COMe (AlaD). The total electrostatic energy associated with 1, 4 and higher interactions is partitioned into atomic contributions by application of quantum chemical topology (QCT). The exact atom-atom interaction is expressed in terms of atomic multipole moments. The machine learning method Kriging is used to model the dependence of these multipole moments on the conformation of the entire molecule. The resulting models are able to predict the QCT-partitioned multipole moments for arbitrary chemically relevant molecular geometries. The interaction energies between atoms are predicted for these geometries and compared to their true values. The computational expense of the procedure is compared to that of the point charge formalism. © 2012 Springer-Verlag.

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