Optimization of Semiempirical Quantum Mechanical Methods for in Silico Drug Design Doctoral thesis Kristian Kříž The subject of this thesis is the optimization of semiempirical quantum mechanical methods (SQM) for their use in in silico drug design. The thesis covers two topics - COSMO2 solvation model optimization part and PLF547, PLA15 dataset development part. The first part is devoted to the optimization of COSMO solvation model by addition of a nonpolar term and reparametrization of the model for SQM methods PM6 and PM7. We have shown that the accuracy of the resulting "COSMO2" optimized model improved on all the tested datasets and we have compared it to other selected SQM solvation models. The method has also been tested on the protein ligand complexes as a part of a scoring function, where it provides better preditction of binding affinity of drug candidates for their target protein. The second part of the thesis describes the construction of datasets for noncovalent interactions aimed speicificly to represent an environment of an enyzme active site complexed with a ligand with reliable benchmark values of interaction energies in vacuum and solvent (water). The developed PLF547 and PLA15 datasets are suitable for testing and development of methods for the use in drug design. We have...

Magnetic ordering of dopants in diamond holds the prospect of exploiting diamond’s unique properties in the emerging field of spintronics. Several transition metal defects have been reported to order ferromagnetically in various semiconductors, however, low Curie temperatures and lack of other fundamental material properties have hindered practical implementation in room temperature spintronic applications. In this Thesis, we consider the energetic stability of 3d transition metal doped-diamond and its magnetic ordering properties at various lattice sites and charge states using ab initio Density Functional Theory methods. We find the majority of 3d transition metal impurities in diamond at any charge state to be energetically most stable at the divacancy site compared to substitutional or interstitial lattice sites, with the interstitial site being highly unstable (by ~8 - 10 eV compared to the divacancy site). At each lattice site and charge state, we find the formation energies of transition metals in the middle of the 3d series (Cr, Mn, Fe, Co, Ni) to be considerably lower compared to those early or late in the series. The energetic stability of transition metal impurities across the 3d series is shown to be strongly dependent on the position of the Fermi level in the diamond band gap, with the formation energies at any lattice site being lower in p-type or ntype diamond compared to intrinsic diamond. Further, we show that incorporation of isolated transition metal impurities into diamond introduces spin polarised impurity bands into the diamond band gap, while maintaining its semiconducting nature, with band gaps in both the spin-up and spin-down channels. These impurity bands are shown to originate mainly from s, p-d hybridization between carbon sp 3 orbitals with the 3d orbitals of the transition metal. In addition, the 4p orbitals contribute significantly to hybridization for transition metal atoms at the substitutional site, but not at the divacancy site. In both cases, the spin polarisation and magnetic stabilization energies are critically dependent on the lattice site and charge state of the transition metal impurity. By allowing magnetic interactions between transition metal atoms, we find that ferromagnetic ordering is likely to be achieved in divacancy Cr+2, Mn+2, Mn+1 and Co0 as well as in substitutional Fe+2 and Fe+1, indicating that transition metal-doped diamond is likely to form a diluted magnetic semiconductor which may successfully be considered for room temperature spintronic applications. In addition, these charge states correspond to p-type diamond, except for divacancy Co0, suggesting that co-doping with shallow acceptors such as B ( will result in an increase of charge concentration, which is likely to enhance mediation of ferromagnetic spin coupling. The highest magnetic stabilization energy occurs in substitutional Fe+1 (33.3 meV), which, also exhibits half metallic ferromagnetic ordering at the Fermi level, with an induced magnetic moment of 1.0 μB per ion, thus suggesting that 100 % spin polarisation may be achieved in Fe-doped diamond. / Physics / D. Litt. et Phil. (Physics)

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) à uma droga usada para tratar o diabetes tipo II (nÃo dependente da insulina), em particular em pessoas cujo diabetes nÃo pode ser controlada sà pelo regime alimentÃcio. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos atravÃs das espectroscopias Raman, infravermelho e infravermelho prÃximo. O objetivo desta investigaÃÃo vibracional à estabelecer correlaÃÃes entre os modos vibracionais e as possÃveis estruturas cristalinas, alÃm de avaliar estes mÃtodos como ferramentas para a identificaÃÃo e controle de qualidade das matÃrias primas e produtos formulados. No intuito de prover uma caracterizaÃÃo detalhada tambÃm empregamos anÃlises tÃrmicas e difraÃÃo de raios- X para a identificaÃÃo prÃvia das formas cristalinas. Finalmente, a classificaÃÃo das bandas observadas nos espectros vibracionais em termos dos modos normais de vibraÃÃo da molÃcula foi realizada com a ajuda de cÃlculos computacionais baseados na teoria do funcional de densidade. Estes resultados tambÃm nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlaÃÃes com o polimorfismo da mesma. / Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug.

Emerging contaminants are defined as synthetic or naturally occurring chemicals or microorganisms that are not currently regulated but have the potential to enter the environment and cause adverse ecological and/or human health effects. With recent development in analytical techniques, emerging contaminants have been detected in wastewater, source water, and finished drinking water. These environmental occurrence data have raised public concern about the fate and ecological impacts of such compounds. Concerns regarding emerging contaminants and the many chemicals that are in use or production necessitate a task to assess their potential health effects and removal efficiency during water treatment. Advanced oxidation processes (AOPs) are attractive and promising technologies for emerging contaminant control due to its capability of mineralizing organic compound via reactions with highly active hydroxyl radicals. However, the nonselective reactivity of hydroxyl radicals and the radical chain reactions make AOPs mechanistically complex processes. In addition, the diversity and complexity of the structure of a large number of emerging contaminants make it difficult and expensive to study the degradation pathways of each contaminant and the fate of the intermediates and byproducts. The intermediates and byproducts that are produced may pose potential effects to human and aquatic ecosystems. Consequently, there is a need to develop first-principle based mechanistic models that can enumerate reaction pathway, calculate concentrations of the byproducts, and estimate their human effects for both water treatment and reuse practices. This dissertation develops methods to predict reaction rate constants for elementary reactions that are identified by a previously developed computer-based reaction pathway generator. Many intermediates and byproducts that are experimentally identified for HO* induced reactions with emerging contaminants include common lower molecular weight organic compounds on the basis of several carbons. These lower carbon intermediates and byproducts also react with HO* at relatively smaller reaction rate constants (i.e., k < 109 M-1s-1) and may significantly affect overall performance of AOPs. In addition, the structures of emerging contaminants with various functional groups are too complicated to model. As a consequence, the rate constant predictors are established based on the conventional organic compounds as an initial approch. A group contribution method (GCM) predicts the aqueous phase hydroxyl radical reaction rate constants for compounds with a wide range of functional groups. The GCM is a first comprehensive tool to predict aqueous phase hydroxyl radical reaction rate constants for reactions that include hydrogen-atom abstraction from a C-H bond and/or a O-H bond by hydroxyl radical, hydroxyl radical addition to a C=C unsaturated bond in alkenes and aromatic compounds, and hydroxyl radical interaction with sulfur-, nitrogen-, or phosphorus-atom-containing compounds. The GCM shows predictability; factor of difference of 2 from literature-reported experimental values. The GCM successfully predicts the hydroxyl radical reaction rate constants for a limited number of emerging contaminants. Linear free energy relationships (LFERs) bridge a kinetic property with a thermochemical property. The LFERs is a new proof-of-concept approach for Ab initio reaction rate constants predictors. The kinetic property represents literature-reported and our experimentally obtained hydroxyl radical reaction rate constants for neutral and ionized compounds. The thermochemical property represents quantum mechanically calculated aqueous phase free energy of activation. Various Ab initio quantum mechanical methods and solvation models are explored to calculate the aqueous phase free energy of activation of reactantas and transition states. The quantum mechanically calculcated aqueous phase free energies of activation are within the acceptable range when compared to those that are obtained from the experiments. These approaches may be applied to other reaction mechanisms to establish a library of rate constant predictions for the mechanistic modeling of AOPs. The predicted kinetic information enables one to identify important pathways of AOP mechanisms that are initiated by hydroxyl radical, and can be used to calculate concentration profiles of parent compounds, intermediates and byproducts. The mechanistic model guides the design of experiments that are used to examine the reaction mechanisms of important intermediates and byproducts and the application of AOPs to real fields.

In this thesis, a survey on pseudospectral methods for differential equations is presented. Properties of the classical orthogonal polynomials required in this context are reviewed. Differentiation matrices corresponding to Jacobi, Laguerre,and Hermite cases are constructed. A fairly detailed investigation is made for the Hermite spectral methods, which is applied to the Schr&ouml / dinger eigenvalue equation with several potentials. A discussion of the numerical results and comparison with other methods are then introduced to deduce the effciency of the method.

xix, 171 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / The field of quantum chaos investigates the quantum mechanical behavior of classically chaotic systems. This dissertation begins by describing an experiment conducted on an apparatus constructed to represent a three dimensional analog of a classically chaotic system. Patterns of reflected light are shown to produce fractals, and the behavior of the fractal dimension D F is shown to depend on the light's ability to escape the apparatus. The classically chaotic system is then used to investigate the conductance properties of semiconductor heterostructures engineered to produce a conducting plane relatively free of impurities and defects. Introducing walls that inhibit conduction to partition off sections considerably smaller than the mean distance between impurities defines devices called 'billiards'. Cooling to low temperatures enables the electrons traveling through the billiard to maintain quantum mechanical phase. Exposure to a changing electric or magnetic field alters the electron's phase, leading to fluctuations in the conductance through the billiard. Magnetoconductance fluctuations in billiards have previously been shown to be fractal. This behavior has been charted using an empirical parameter, Q , that is a measure of the resolution of the energy levels within the billiard. The relationship with Q is shown to extend beyond the ballistic regime into the 'quasi-ballistic' and 'diffusive' regimes, characterized by having defects within the conduction plane. A model analogous to the classically chaotic system is proposed as the origin of the fractal conductance fluctuations. This model is shown to be consistent with experiment and to account for changes of fine scale features in MCF known to occur when a billiard is brought to room temperature between low temperature measurements. An experiment is conducted in which fractal conductance fluctuations (FCF) are produced by exposing a billiard to a changing electric field. Comparison of D F values of FCF produced by electric fields is made to FCF produced by magnetic fields. FCF with high D F values are shown to de-correlate at smaller increments of field than the FCF with lower D F values. This indicates that FCF may be used as a novel sensor of external fields, so the response of FCF to high bias voltages is investigated. / Adviser: Stephen Kevan, Chairperson, Physics; Richard Taylor, Advisor, Physics; Robert Zimmerman, Member, Physics; Stephen Gregory, Member, Physics; David Johnson, Outside Member, Chemistry

Magnetic ordering of dopants in diamond holds the prospect of exploiting diamond’s unique properties in the emerging field of spintronics. Several transition metal defects have been reported to order ferromagnetically in various semiconductors, however, low Curie temperatures and lack of other fundamental material properties have hindered practical implementation in room temperature spintronic applications. In this Thesis, we consider the energetic stability of 3d transition metal doped-diamond and its magnetic ordering properties at various lattice sites and charge states using ab initio Density Functional Theory methods. We find the majority of 3d transition metal impurities in diamond at any charge state to be energetically most stable at the divacancy site compared to substitutional or interstitial lattice sites, with the interstitial site being highly unstable (by ~8 - 10 eV compared to the divacancy site). At each lattice site and charge state, we find the formation energies of transition metals in the middle of the 3d series (Cr, Mn, Fe, Co, Ni) to be considerably lower compared to those early or late in the series. The energetic stability of transition metal impurities across the 3d series is shown to be strongly dependent on the position of the Fermi level in the diamond band gap, with the formation energies at any lattice site being lower in p-type or ntype diamond compared to intrinsic diamond. Further, we show that incorporation of isolated transition metal impurities into diamond introduces spin polarised impurity bands into the diamond band gap, while maintaining its semiconducting nature, with band gaps in both the spin-up and spin-down channels. These impurity bands are shown to originate mainly from s, p-d hybridization between carbon sp 3 orbitals with the 3d orbitals of the transition metal. In addition, the 4p orbitals contribute significantly to hybridization for transition metal atoms at the substitutional site, but not at the divacancy site. In both cases, the spin polarisation and magnetic stabilization energies are critically dependent on the lattice site and charge state of the transition metal impurity. By allowing magnetic interactions between transition metal atoms, we find that ferromagnetic ordering is likely to be achieved in divacancy Cr+2, Mn+2, Mn+1 and Co0 as well as in substitutional Fe+2 and Fe+1, indicating that transition metal-doped diamond is likely to form a diluted magnetic semiconductor which may successfully be considered for room temperature spintronic applications. In addition, these charge states correspond to p-type diamond, except for divacancy Co0, suggesting that co-doping with shallow acceptors such as B ( will result in an increase of charge concentration, which is likely to enhance mediation of ferromagnetic spin coupling. The highest magnetic stabilization energy occurs in substitutional Fe+1 (33.3 meV), which, also exhibits half metallic ferromagnetic ordering at the Fermi level, with an induced magnetic moment of 1.0 μB per ion, thus suggesting that 100 % spin polarisation may be achieved in Fe-doped diamond. / Physics / D. Litt. et Phil. (Physics)

Increasing energy demand draws attention to new materials for improving current energy storage technologies. Particular interest is directed at solid state batteries and glass Na3ClO electrolyte is a promising candidate. In this report we explore some of the properties of this new glass and its capabilities as a potential electrolyte for a solid-state battery. The two aims of the study were to model the amorphous structure of the glass using the stochastic quenching method based on density functional theory as well as assessing the electrochemical stability of it against a metallic sodium electrode. Using VASP, a computational code based on density functional theory, we performed calculations of two 150 atom supercells, where the atoms were moved around until the systems were relaxed to obtain two glass models and the resulting structures were analyzed and characterized. The characterization of the structures was made by means of partial radial distribution functions, angle distribution functions, coordination numbers and bond lengths, which showed that the two models are statistically equivalent and either one can be used for the stability assessment of the glass. The electrochemical stability was assessed by inserting an extra sodium atom in possible holes in the glass model and calculating the energetics of Na insertion in each of these holes. This was made for 30 different hole positions. The reduction potential indicates the stability of each hole and the results was plotted as an energy distribution. Two peaks in the energy distribution, located at positive and negative energies, indicating stable and unstable holes, respectively. This indicates that the amorphous structure of the glass allows Na ions to travel (unstable holes). The stable peak has a greater probability density, which indicates a stable electrolyte against sodium metal electrode, though a larger sampling of holes is required for better statistics. / Ökande krav på energiefterfrågan uppmärksammar nya material för att förbättra nuvarande energilagringsteknik, med fokus på solida batterier och glaset Na3ClO som en lovande kandidat för elektrolyt. I denna rapport undersöks några av egenskaperna för glaset samt möjligheten för denna att fungera som elektrolyt i ett solid-state batteri. Målen med projektet var att modellera den amorfa strukturen av glaset genom att använda stochastic quenching method som baseras på density functional theory samt undersöka den elektrokemiska stabiliteten mot en metallisk natrium elektrod. Genom användning av VASP, beräkningskoder baserade på density functional theroy, beräknades två superceller med 150 atomer vardera där atomerna flyttas runt tills dess att systemet var relaxerat och två modeller av glaset erhölls. Dessa var sedan visualiserades och karakteriserade. Karakterisering av strukturerna gjordes genom en partiella radiella fördelningsfunktioner, vinkel distrubitionsfunktioner, koordinationsnummer och bindningslängder. Detta visade på statistisk ekvivalens, vilket innebär att båda modellerna kan användas för vidare stabilitetsundersökning. Den elektrokemiska stabiliteten undersöktes genom att sätta in en extra natrium atom i möjliga hål i glas modellen samt beräkna dess energier av Na insättning i respektive hål. Detta gjordes för 30 olika positioner för hålen. Reduktionspotentialen indikerar stabiliteten för respektive hål, och resultatet plottades som en energidistribution. Två toppar i energidistributionen, lokaliserade vid positiva och negativa energier, indikerar stabila respeltive instabila hål. Detta indikerar på att den amorfa strukturen för glaset tillåter Na joner att färdas (instabila hål). Den stabila toppen har en större sannolikhetstäthet vilket indikerar på en stabil elektrolyt mot en metallisk natrium elektrod, men en större samling hål krävs för en bättre statistisk säkerhet.

Indiana University-Purdue University Indianapolis (IUPUI) / Molecular polarizability plays a significant role in chemistry, biology, and medicine. Classical prediction of polarizability often relies on atomic-type specific polarizability optimized for training set molecules, which limits the calculations to systems of similar chemical environment. Although ab initio (AI) quantum mechanical (QM) methods are more transferable in predicting molecular polarizability, their high computational costs especially when used with large basis sets for obtaining quantitatively reliable results make them less practical. To obtain accurate QM polarizability in an efficient manner, we have developed a dual-level approach, where the polarizability (α) obtained from the efficient semiempirical QM (SE) method is corrected using a set of element-base atomic polarizabilities derived from the atomic dipole interaction model (ADIM) to reproduce the density functional theory (DFT) results. We have optimized the atomic polarizability correction parameters for CHON-containing systems using a small training set of molecules and tested the resulting SE-ADIM model on the neutral drug-like molecules in the QM7B database. SE-ADIM corrected AM1 showed substantial improvement with its relative percent error (RPE) compared to B3LYP reduced from 33.81% to 3.35%. To further test its robustness for larger molecules in broader chemical bonding situations, we applied this method to a collection of drug molecules from the e-Drug3D database. For the 1004 molecules tested, our SE-ADIM model, which only contains four empirical parameters, greatly reduces the RPE in AM1 polarizability relative to B3LYP from 26.8% to 2.9%. Error decomposition shows consistent improvements across molecules with diverse bond saturations, molecular sizes, and charge states. In addition, we have applied AlphaML, a promising machine learning (ML) technique for predicting molecular polarizability, to the e-Drug3D dataset to compare its performance with our SE-ADIM correction of AM1. We found SE-ADIM performs competitively with AlphaML bolstering our confidence in the value of our method. Errors distinct to AlphaML were also discovered. We found four molecules for which AlphaML predicts negative molecular polarizabilities, all of which were peroxides. In contrast, SE-ADIM has no such issue with these molecules or this chemical type. Finally, to improve performance of SE-ADIM when correcting AM1 molecular polarizability calculations for charged molecules, we introduce a charge dependent polarizability (CDP) enabled SE-ADIM. Training the CDP enabled SE-ADIM with a single additional parameter, B, we were able to reduce error in AM1 molecular polarizability calculations of charged molecules relative to B3LYP from 29.57% to 5.16%. By contrast, SE-ADIM without CDP corrected AM1 relative to B3LYP had an RPE of 8.56%. The most benefit of CDP was evident within negatively charged molecules where AM1 error relative to B3LYP fell from 32.20% to 3.77% while SE-ADIM without CDP enabled error for these same negative molecules was 10.06%.

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