Transferable atomic multipole machine learning models for small organic molecules

Accurate representation of the molecular electrostatic potential, which is often expanded in distributed multipole moments, is crucial for an efficient evaluation of intermolecular interactions. Here we introduce a machine learning model for multipole coefficients of atom types H, C, O, N, S, F, and Cl in any molecular conformation. The model is trained on quantum chemical results for atoms in varying chemical environments drawn from thousands of organic molecules. Multipoles in systems with neutral, cationic, and anionic molecular charge states are treated with individual models. The models' predictive accuracy and applicability are illustrated by evaluating intermolecular interaction energies of nearly 1,000 dimers and the cohesive energy of the benzene crystal.Comment: 11 pages, 6 figure

On the prediction of partition coefficients using the statistical associating fluid theory underpinned by quantum mechanical calculations

The thermodynamic modelling of phase equilibrium is of central importance in chemical engineering applications. The design, operation and develop- ment of new chemical processes is based to a large extent on the knowledge of the equilibrium that occurs between co-existing fluid phases. Where re- liable experimental data at required process conditions is unavailable, an understanding of the molecular description of condensed phase matter is key to predicting the thermodynamic properties of these fluid systems. To this end, numerous models and theories have been developed that seek to link microscopic intermolecular interactions with bulk macroscopic thermo- dynamic properties. In this thesis, two such constructs for the prediction of phase equilibrium are considered. The empirical linear solvation energy relationship (LSER) that relates specific/unspecific intermolecular interac- tions to infinite dilution solute properties, and equations of state (EoS) for the prediciton of vapour-liquid and liquid-liquid equilibrium. The LSER model utilises hydrogen bond acceptor/donor parameters (A and B) alongside polarisability (S), volume (V) and molar refraction (E) param- eters to describe various solute properties. In this study, the prediciton of solute infinite dilution partititon coefficient is of particular interest. While the V and E parameters can be obtained from molecular structure calcula- tions that account for the number of atoms and bonds in a molecule, the re- maining LSER parameters are usually derived from chromatographic experiments. However, successive studies have successfully correlated and pre- dicted the hydrogen bonding parameters from quantum mechanical (QM) calculated molecular properties, enabling the rapid calculation of infinite dilution solute properties in the so-called QM/LSER approach. In this the- sis, two independent linear regression relationships that relate theoretically calculated hydrogen bond stabilisation energies at a donor and/or acceptor site(s) to experimental hydrogen bonding ability of a solute molecule have been determined. Once obtained, the solute hydrogen bonding parameters are used in conjunction with dispersion and volume parameters in the LSER to obtain solute partition coefficients. Using this approach ,the octanol/wa- ter partition coefficients of various molecules have been estimated, of this, the absolute average error of a sub-set of straight chained, mono-functional solute molecules has been determined to be 23.04% when compared to ex- perimental data. The second approach to modeling condensed phased matter is based on the statistical associating fluid theory (SAFT), a molecular-based equation of state with a foundation in statistical mechanics. Here, a recently devel- oped group-contribution version i.e., SAFT-1 is considered. The SAFT-1 EoS has been successfully applied in the prediction of the octanol/water patition coefficients of a range of solute molecules that include n-alkane, n-alkene, 2- ketone and n-amine molecules. Where the average absolute error of SAFT- 1 predicitons when compared to experimental data is found to be 13.20%. However, as with other EoS, SAFT-1 is dependent on experimental data re- quired to parameterise the various groups that make up the fluid/fluid mix- ture under investigation. The aim of this work is to increase the predictive ability of SAFT-1 by reducing dependence on experimental data, whereby in- stead of equilibrium data, solute partition coefficients estimated using the QM/LSER method are used to parameterise the relevant molecular groups. In the final part of the thesis, the proposed hypothesis of combining the QM/LSER and SAFT-1 methods is tested with the aim of predicting the phase behaviour of binary mixtures. The method relies on the calculation of partition coefficients using QM and LSER, the calculated partition coef- ficients are then used to parameterise the unlike group-group interactions required for the prediction of binary mixture behaviour in SAFT-1. This methodology has been validated using the n-aldehyde and 2-ketone chemi- cal families, where using QM/LSER to parameterise SAFT-1 has been found to achieve results that are comparative to the classical empirical approach of parameterising the SAFT-1 EoS when predicting binary phase behaviour. The unlike group interaction parameters for the SAFT-1 EoS have been suc- cessfully parameterised using partition coefficient data estimated from the- oretically calculated quantum mechanical molecular properties. However, the solutes considered in this study are limited to linear mono-functional molecules. The reason for this limitation is two fold. Firstly, predicting hydrogen bond parameters of multi-functional molecules is unreliable mainly as a consequence of polarisation of H-bond sites due to the proximity of functional groups. Therefore a better understanding of how polarisation affects hydrogen bonding is required. Secondly, within SAFT-1 the major- ity of available groups are for modeling linear mono-functional molecules. However there is continuing work to model both branched and multifunc- tional molecules. Once both of these concerns are effectively dealt with, the proposed methodology can be used to characterize a wider range of SAFT- 1 groups and predict thermodynamic behaviour of molecules based on QM molecular calculations.Open Acces

Physicochemical property prediction for small molecules using integral equation-based solvation models

In this thesis the accurate prediction of physicochemical properties of small, pharmaceutically relevant compounds is investigated. To predict condensed phase properties such as hydration free energies, acid dissociation constants (pKa), and distribution and partition coefficients (log D and log P, respectively) it is necessary to accurately describe the solute, the solute-solvent interactions, and the solvent-response to the solute’s presence. When this is achieved, the Gibbs energies of the molecules in solution can be used to calculate macroscopic physicochemical properties. The embedded cluster reference interaction site model (EC-RISM) makes it possible to combine a quantum chemical description of the solute with an accurate solvent response via the three-dimensional reference interaction site model (3D RISM). This is ideal for calculating physicochemical properties of small molecules, because EC RISM yields both the electronic energy of the solvent-polarized wave function, as well as the excess chemical potential of the molecule in solution, the sum of which can be defined as the Gibbs energy of the molecule in solution. The development of solvent susceptibilities for the non-aqueous solvents cyclohexane and n octanol is reported, as well as the challenges and implications of including water saturation for organic solvents. The solvent susceptibilities are used to train partial molar volume corrections to correct for the error inherent in the calculation of the 3D RISM excess chemical potential using reference data from the Minnesota solvation database (MNSOL). Additionally, a method to calculate accurate pKa values is presented and the formal equivalence of a microstate transition and a partition function approach is briefly summarized. The performance of the models is benchmarked by participation in the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges. First, the SAMPL5 challenge, where cyclohexane-water distribution coefficients log D7.4 had to be calculated. In subsequent challenges the task was split into determining aqueous pKa values during the SAMPL6 challenge and octanol-water partition coefficients log P of a subset of these compounds for SAMPL6 part II. Over the course of these challenges a number of key improvements were made to the EC RISM model, often directly as a result of inconsistencies or performance issues during one of the SAMPL challenges. Finally, an extension of the partial molar volume correction to extreme conditions such as high pressure is reported

Prediction of partition coefficients for systems of micelles using DFT

[eng] A compound’s solvent−water partition coefficient (log P) measures the equilibrium ratio of the compound’s concentrations in a two-phase system: as two solvents in contact or a system of micelles in an aqueous solution. In this thesis, the partition coefficient of three groups of small compounds (alcohol, ether, and hydrocarbons) in 10 different solvents (benzene, cyclohexane, hexane, n-Octane, toluene, carbon tetrachloride, heptane, trichloroethane, and octanol) was computed used DFT and B3LYP method with 6.31G(d), 6.311+G** and 6.311++G** basis sets. It is obtained that the partition coefficient of alcohol solutes in various solvents using the 6.31G(d) basis set indicates a satisfactory correlation with experimental values. The correlation between the experimental value and the partition coefficient of ether solutes in different solvents using the 6.311++G** basis set shows high agreement. The experimental data displayed a high correlation with the partition coefficient computed for hydrocarbon compounds in various solvents using all three basis sets: 6.31G(d), 6.311+G**, and 6.311++G**. In addition, we have studied the correlation of the experimental partition coefficients in Sodium Dodecyl Sulfate (SDS), Hexadecyltrimethylammonium bromide (HTAB), Sodium cholate (SC), and Lithium perfluoro octane sulfonate (LPFOS) micelles with ab initio calculated partition coefficients in 15 different organic solvents. Specifically, the partition coefficients of a series of 63 molecules in an aqueous system of SDS, SC, HTAB, and LPFOS micelles are correlated with the partition coefficient in heptane/water, cyclohexane/water, n-dodecane/water, pyridine/water, acetic acid/water, octanol/water, acetone/water, 1-propanol/water, 2-propanol/water, methanol/water, formic acid/water, diethyl sulfide/water, decan-1-ol/water, 1-2 ethane diol/water and dimethyl sulfoxide/water systems. All calculations were performed using the Gaussian 16 Quantum Chemistry package. Molecular structures were generated in the more extended conformation using Avogadro, and geometries of all molecules were optimized using Density Functional Theory (DFT) B3LYP and MO6-2X with 6-31++G** basis set by the continuum solvation model based on density (SMD). The obtained results show that calculated partition coefficients in the alcohol/water mixture give the best correlation to predict the experimental partition coefficients in SDS, SC, and LPFOS micelles. With respect to HTAB micelle systems, a new selection of molecules is created, excluding those containing N atoms and Urea atom groups. Interestingly, the partition coefficient of these chosen molecules exhibits a strong correlation with the experimental partition coefficient. Finally, the partition coefficient of flexible molecules was studied by the same protocol for two solvent combinations, octanol/water and cyclohexane/water. The calculated values were compared with the experimental partition coefficients. The average partition coefficient in octanol solvent exhibited a high correlation with the experimental data. However, for the 16 compounds in the cyclohexane solvent, their partition coefficients do not exhibit significant agreement with the experimental partition coefficients.[cat] S'ha desenvolupat una metodologia computacional per calcular el coeficient de partició de diferents tipus de molècules en sistemes micel·lars. En primer lloc, s'ha calculat el coeficient de partició de tres grups de compostos (alcohol, èter i hidrocarburs) utilitzant el mètode DFT amb el funcional B3LYP. S'han obtingut correlacions satisfactòries amb els valors experimentals. En aquesta tesi s'ha desenvolupat un procediment per calcular els coeficients de partició experimentals en micel·les de dodecilsulfat de sodi (SDS), bromur d'hexadeciltrimetilamoni (HTAB), colat de sodi (SC) i perfluorooctanosulfonat de liti (LPFOS). Específicament, els coeficients de partició d'una sèrie de 63 molècules en un sistema aquós de micel·les de SDS, SC, HTAB i LPFOS es correlacionen amb el coeficient de partició en deu barreges aquoses. Els resultats obtinguts mostren que els coeficients de partició calculats a la barreja alcohol/aigua donen la millor correlació per predir els coeficients de partició experimentals en micel·les SDS, SC i LPFOS. Pel que fa als sistemes micelars HTAB, es crea una nova selecció de molècules, excloent-ne aquelles que contenen àtoms de N aromàtics i grups d'urea. És interessant notar que el coeficient de partició d'aquestes molècules triades mostra una forta correlació amb el coeficient de partició experimental. Finalment, es va estudiar el coeficient de partició de molècules flexibles mitjançant el mateix protocol per a dues combinacions de dissolvents, octanol/aigua i ciclohexà/aigua. Els valors calculats es van comparar amb els coeficients de partició experimentals. El coeficient de partició mitjana en dissolvent octanol va mostrar una alta correlació amb les dades experimentals. Tot i això, per als 16 compostos en el dissolvent ciclohexà, els seus coeficients de partició no mostren una concordança significativa amb els coeficients de partició experimental

Prediction of partition coefficients for systems of micelles using DFT

Programa de Doctorat en Química Teòrica i Modelització Computacional[eng] A compound’s solvent−water partition coefficient (log P) measures the equilibrium ratio of the compound’s concentrations in a two-phase system: as two solvents in contact or a system of micelles in an aqueous solution. In this thesis, the partition coefficient of three groups of small compounds (alcohol, ether, and hydrocarbons) in 10 different solvents (benzene, cyclohexane, hexane, n-Octane, toluene, carbon tetrachloride, heptane, trichloroethane, and octanol) was computed used DFT and B3LYP method with 6.31G(d), 6.311+G** and 6.311++G** basis sets. It is obtained that the partition coefficient of alcohol solutes in various solvents using the 6.31G(d) basis set indicates a satisfactory correlation with experimental values. The correlation between the experimental value and the partition coefficient of ether solutes in different solvents using the 6.311++G** basis set shows high agreement. The experimental data displayed a high correlation with the partition coefficient computed for hydrocarbon compounds in various solvents using all three basis sets: 6.31G(d), 6.311+G**, and 6.311++G**. In addition, we have studied the correlation of the experimental partition coefficients in Sodium Dodecyl Sulfate (SDS), Hexadecyltrimethylammonium bromide (HTAB), Sodium cholate (SC), and Lithium perfluoro octane sulfonate (LPFOS) micelles with ab initio calculated partition coefficients in 15 different organic solvents. Specifically, the partition coefficients of a series of 63 molecules in an aqueous system of SDS, SC, HTAB, and LPFOS micelles are correlated with the partition coefficient in heptane/water, cyclohexane/water, n-dodecane/water, pyridine/water, acetic acid/water, octanol/water, acetone/water, 1-propanol/water, 2-propanol/water, methanol/water, formic acid/water, diethyl sulfide/water, decan-1-ol/water, 1-2 ethane diol/water and dimethyl sulfoxide/water systems. All calculations were performed using the Gaussian 16 Quantum Chemistry package. Molecular structures were generated in the more extended conformation using Avogadro, and geometries of all molecules were optimized using Density Functional Theory (DFT) B3LYP and MO6-2X with 6-31++G** basis set by the continuum solvation model based on density (SMD). The obtained results show that calculated partition coefficients in the alcohol/water mixture give the best correlation to predict the experimental partition coefficients in SDS, SC, and LPFOS micelles. With respect to HTAB micelle systems, a new selection of molecules is created, excluding those containing N atoms and Urea atom groups. Interestingly, the partition coefficient of these chosen molecules exhibits a strong correlation with the experimental partition coefficient. Finally, the partition coefficient of flexible molecules was studied by the same protocol for two solvent combinations, octanol/water and cyclohexane/water. The calculated values were compared with the experimental partition coefficients. The average partition coefficient in octanol solvent exhibited a high correlation with the experimental data. However, for the 16 compounds in the cyclohexane solvent, their partition coefficients do not exhibit significant agreement with the experimental partition coefficients.[cat] S'ha desenvolupat una metodologia computacional per calcular el coeficient de partició de diferents tipus de molècules en sistemes micel·lars. En primer lloc, s'ha calculat el coeficient de partició de tres grups de compostos (alcohol, èter i hidrocarburs) utilitzant el mètode DFT amb el funcional B3LYP. S'han obtingut correlacions satisfactòries amb els valors experimentals. En aquesta tesi s'ha desenvolupat un procediment per calcular els coeficients de partició experimentals en micel·les de dodecilsulfat de sodi (SDS), bromur d'hexadeciltrimetilamoni (HTAB), colat de sodi (SC) i perfluorooctanosulfonat de liti (LPFOS). Específicament, els coeficients de partició d'una sèrie de 63 molècules en un sistema aquós de micel·les de SDS, SC, HTAB i LPFOS es correlacionen amb el coeficient de partició en deu barreges aquoses. Els resultats obtinguts mostren que els coeficients de partició calculats a la barreja alcohol/aigua donen la millor correlació per predir els coeficients de partició experimentals en micel·les SDS, SC i LPFOS. Pel que fa als sistemes micelars HTAB, es crea una nova selecció de molècules, excloent-ne aquelles que contenen àtoms de N aromàtics i grups d'urea. És interessant notar que el coeficient de partició d'aquestes molècules triades mostra una forta correlació amb el coeficient de partició experimental. Finalment, es va estudiar el coeficient de partició de molècules flexibles mitjançant el mateix protocol per a dues combinacions de dissolvents, octanol/aigua i ciclohexà/aigua. Els valors calculats es van comparar amb els coeficients de partició experimentals. El coeficient de partició mitjana en dissolvent octanol va mostrar una alta correlació amb les dades experimentals. Tot i això, per als 16 compostos en el dissolvent ciclohexà, els seus coeficients de partició no mostren una concordança significativa amb els coeficients de partició experimental

Poisson-Boltzmann Theory of Charged Colloids: Limits of the Cell Model for Salty Suspensions

Thermodynamic properties of charge-stabilised colloidal suspensions are commonly modeled by implementing the mean-field Poisson-Boltzmann (PB) theory within a cell model. This approach models a bulk system by a single macroion, together with counterions and salt ions, confined to a symmetrically shaped, electroneutral cell. While easing solution of the nonlinear PB equation, the cell model neglects microion-induced correlations between macroions, precluding modeling of macroion ordering phenomena. An alternative approach, avoiding artificial constraints of cell geometry, maps a macroion-microion mixture onto a one-component model of pseudo-macroions governed by effective interactions. In practice, effective-interaction models are usually based on linear screening approximations, which can accurately describe nonlinear screening only by incorporating an effective (renormalized) macroion charge. Combining charge renormalization and linearized PB theories, in both the cell model and an effective-interaction (cell-free) model, we compute osmotic pressures of highly charged colloids and monovalent microions over a range of concentrations. By comparing predictions with primitive model simulation data for salt-free suspensions, and with predictions of nonlinear PB theory for salty suspensions, we chart the limits of both the cell model and linear-screening approximations in modeling bulk thermodynamic properties. Up to moderately strong electrostatic couplings, the cell model proves accurate in predicting osmotic pressures of deionized suspensions. With increasing salt concentration, however, the relative contribution of macroion interactions grows, leading predictions of the cell and effective-interaction models to deviate. No evidence is found for a liquid-vapour phase instability driven by monovalent microions. These results may guide applications of PB theory to soft materials.Comment: 27 pages, 5 figures, special issue of Journal of Physics: Condensed Matter on "Classical density functional theory methods in soft and hard matter