On the Use of the Linear Interaction Energy Method to Predict Affinities of Charged Aromatic Ammines to Naturally Occurring Clay Minerals

This study presents the use of the linear interaction energy (LIE) method as a predictive tool to approximate the free energies of sorption of organic cations to naturally occurring clay mineral montmorillonite. One objective of this thesis is to explore the applicability and the accuracy of LIE, originated in the biochemistry field, as a predictive tool to estimate the free energies of sorption of organic cations to naturally occurring aluminosilicates. For this purpose, a set of charged aromatic amines sorbing to a prototypical homoionic clay montmorillonite (MMT) with calcium ions were modeled using molecular dynamics (MD) simulations. As the LIE method enables the inclusion of both electrostatic and van der Waals interactions of the sorbate (organic cation) with the negatively charged aluminosilicate (sorbent), it provided a major improvement over existing predictive models which underestimates the sorption free energies due to exclusion of electrostatic interactions. Moreover, Use of MD simulations and electronic structure calculations provided atomistic level insight into the orientation of different organic cations inside the clay and their charge distribution. This thesis also explores the transferability of the derived LIE parameters as a function of different interlayer ions: Ca+2 and Na+ in MMT

APPLICATION OF LINEAR FREE ENERGY RELATIONSHIPS IN THE PREDICTION OF TRIGLYCERIDE/WATER PARTITION COEFFICIENTS AND LIPID BILAYER PERMEABILITY COEFFICIENTS OF SMALL ORGANIC MOLECULES AND PEPTIDES

Computational methods such as linear free energy relationships (LFERs) offer a useful high-throughput solution to quickly evaluate drug developability, e.g. membrane permeability, organic solvent/water partition coefficients, and solubility. LFERs typically assume the contribution of structural components/functional groups to the overall properties of a given molecule to be constant and independent. This dissertation describes a series of studies in which linear free energy relationships were developed to predict solvation of small organic molecules in lipid formulations, specifically, triglyceride containing solvents and phospholipid-based liposomes. The formation of intermolecular HBs in triglyceride solvents (homogenous with H-bond accepting ability) and intramolecular HBs within the bilayer barrier domain (hydrocarbon-like) proved to be the major factors to consider in developing LFERs to account for the increased oil/water partition coefficients and enhanced bilayer permeability of small organic molecules. The triglyceride solvent/water partition coefficients of a series of model compounds varying in polarity and H-bond donating/accepting capability were used to establish a correlation between the solvent descriptors and the ester concentration in these solvents using the Abraham LFER approach. The LFER analyses showed that the descriptors representing the polarizability and H-bond basicity of the solvents vary systematically with the ester concentration. A fragment-based LFER to predict membrane permeability or 1,9- decadiene/water partition coefficients of small organic molecules including small peptides was systematically constructed using a total of 47 compounds. Significant nonadditivity was observed in peptides in that the contribution of the peptide backbone amide to the apparent transfer free energy from water into the bilayer barrier domain is considerably smaller than that of a “well-isolated” amide and greatly affected by adjacent polar substituents on the C-termini. In order to explain the phenomenon of nonadditivity, the formation of intramolecular HBs and inductive effects of neighboring polar groups on backbone amide, were investigated using FTIR and MD simulations. Both spectroscopic and computational results provided supportive evidence for the hypothesis that the formation of intramolecular HBs in peptides is the main reason for the observed nonadditivity of Δ(ΔG°)-CONH-. The MD simulation results showed that the inductive effect of neighboring groups is not as important as the effect of intramolecular HBs

Quantitative structure-property relationships for predicting group IIB metal binding by organic ligands

Mercury (Hg), cadmium (Cd), and zinc (Zn) in the environment are all of toxicological and environmental concern, and the pollution of natural waters by any of these three elements is most serious. Mercury is the most environmentally concerning of the three because of the neurotoxin species monomethylmercury produced in aquatic systems through the methylation of Hg2+ by aquatic microorganisms. An important chemical process in natural waters that limits the availability of mercury for methylation is the binding of Hg(II) by natural organic matter (NOM). These associations are exceptionally strong, and as NOM is ubiquitous in aquatic environments, estimating equilibrium constants for Hg(II) binding to NOM in natural waters is important. Cadmium is moderately toxic to all organisms, and skeletal damage caused by exposure to cadmium-contaminated water has been reported. Also high concentrations of zinc that are toxic or even lethal to organisms have been observed in natural waters. As the free ion forms of cadmium and zinc in natural waters are thought to be most toxic, Cd(II) and Zn(II) complexation by NOM and estimating the complexation equilibrium constants are, similarly to Hg(II), of interest. With experimental determination of M(II)-NOM (M = Hg, Cd, Zn) binding constants being costly and time consuming, it is desirable to estimate those constants without the benefit of additional experimental data. This work uses QSPRs (Quantitative Structure-Property Relationships) to predict binding constants from hypothetical structures of NOM molecules. For the first time, to our knowledge, a QSPR for predicting Hg(II) complexation by organic ligands has been developed. Also two QSPRs for predicting Cd(II) and Zn(II) complexation by organic ligands, that had been developed earlier, have been improved to be capable of predicting the binding of Cd(II) and Zn(II) to thiol-containing molecules. Most of the compounds used in the calibration data sets of the three QSPRs contained some or all of carboxylate, amine, and thiol ligand groups. The Hg(II), Cd(II), and Zn(II) QSPRs respectively have standard error of prediction (Spred) values of 1.60, 0.935, and 0.984 log units and describe 96.5%, 93.1%, and 93.4% of the variability in data. The most noteworthy observation in the developed QSPRs was the exceptionally high affinity Hg(II) had for thiols. Although thiols form a very small fraction of NOM, this binding is considerably important because of its strength. This work also presents certain potential applications of the developed QSPRs in predicting M(II)-NOM binding as well as predicting M(II) binding to organic molecules which would be synthesized for M(II) remediation and chelation therapy

Improving Performance of the SMD Solvation Model: Bondi Radii Improve Predicted Aqueous Solvation Free Energies of Ions and pK\u3csub\u3ea\u3c/sub\u3e Values of Thiols

Calculation of the solvation free energy of ionic molecules is the principal source of errors in the quantum chemical evaluation of pKa values using implicit polarizable continuum solvent models. One of the important parameters affecting the performance of these models is the choice of atomic radii. Here, we assess the performance of the solvation model based on density (SMD) implicit solvation model employing SMD default radii (SMD) and Bondi radii (SMD-B), a set of empirical atomic radii developed based on the crystallographic data. For a set of 112 ions (60 anions and 52 cations), the SMD-B model showed lower mean unsigned error (MUE) for predicted aqueous solvation free energies (4.0 kcal/mol for anions and 2.4 kcal/mol for cations) compared to the standard SMD model (MUE of 5.0 kcal/mol for anions and 2.9 kcal/mol for cations). In particular, usage of Bondi radii improves the aqueous solvation energies of sulfur-containing ions by \u3e5 kcal/mol compared to the SMD default radii. Indeed, for a set of 45 thiols, the SMD-B model was found to dramatically improve the predicted pKa values, with ∼1 pKa unit mean deviation from the experimental values, compared to ∼7 pKa units mean deviation for the SMD model with the default radii. These findings highlight the importance of the choice of atomic radii on the performance of the implicit solvation models

Basic Research Needs for Geosciences: Facilitating 21st Century Energy Systems

Executive Summary Serious challenges must be faced in this century as the world seeks to meet global energy needs and at the same time reduce emissions of greenhouse gases to the atmosphere. Even with a growing energy supply from alternative sources, fossil carbon resources will remain in heavy use and will generate large volumes of carbon dioxide (CO2). To reduce the atmospheric impact of this fossil energy use, it is necessary to capture and sequester a substantial fraction of the produced CO2. Subsurface geologic formations offer a potential location for long-term storage of the requisite large volumes of CO2. Nuclear energy resources could also reduce use of carbon-based fuels and CO2 generation, especially if nuclear energy capacity is greatly increased. Nuclear power generation results in spent nuclear fuel and other radioactive materials that also must be sequestered underground. Hence, regardless of technology choices, there will be major increases in the demand to store materials underground in large quantities, for long times, and with increasing efficiency and safety margins. Rock formations are composed of complex natural materials and were not designed by nature as storage vaults. If new energy technologies are to be developed in a timely fashion while ensuring public safety, fundamental improvements are needed in our understanding of how these rock formations will perform as storage systems. This report describes the scientific challenges associated with geologic sequestration of large volumes of carbon dioxide for hundreds of years, and also addresses the geoscientific aspects of safely storing nuclear waste materials for thousands to hundreds of thousands of years. The fundamental crosscutting challenge is to understand the properties and processes associated with complex and heterogeneous subsurface mineral assemblages comprising porous rock formations, and the equally complex fluids that may reside within and flow through those formations. The relevant physical and chemical interactions occur on spatial scales that range from those of atoms, molecules, and mineral surfaces, up to tens of kilometers, and time scales that range from picoseconds to millennia and longer. To predict with confidence the transport and fate of either CO2 or the various components of stored nuclear materials, we need to learn to better describe fundamental atomic, molecular, and biological processes, and to translate those microscale descriptions into macroscopic properties of materials and fluids. We also need fundamental advances in the ability to simulate multiscale systems as they are perturbed during sequestration activities and for very long times afterward, and to monitor those systems in real time with increasing spatial and temporal resolution. The ultimate objective is to predict accurately the performance of the subsurface fluid-rock storage systems, and to verify enough of the predicted performance with direct observations to build confidence that the systems will meet their design targets as well as environmental protection goals. The report summarizes the results and conclusions of a Workshop on Basic Research Needs for Geosciences held in February 2007. Five panels met, resulting in four Panel Reports, three Grand Challenges, six Priority Research Directions, and three Crosscutting Research Issues. The Grand Challenges differ from the Priority Research Directions in that the former describe broader, long-term objectives while the latter are more focused

Synergism between organic and inorganic moieties: in the search of new hybrid materials for optics and biomedicine

232 p.In this work different versatile photoactive hybrid materials with interesting features for optics and biomedicine are achieved and exhaustively characterized. Firstly, by means of the occlusion of different fluorescent dyes, by the crystallization inclusion method, into several 1D-channeled magnesium aluminophosphate (MgAPO) hosts (with different sized and shaped pores), optically dense fluorescent hybrid materials which show highly anisotropic response to linearly polarized light are obtained. Depending on the dye embedded within the selected MgAPO framework, interesting applications have been attained, such as one-directional artificial photonic antenna systems covering the whole UV-Visible spectral range, Second Harmonic Generators under NIR radiation, optically switchable hybrid systems and white light emitters. White light emission is also obtained from the luminescence that arises from embedding simultaneously different small aromatic molecules into a Metal Organic Framework (MOF), named [Zn2(bdc)2(dpNDI)]n, which contains a photoactive naphtalemediimide as organic pillar. The incorporation of halide-substituted aromatic molecules into this MOF also promotes phosphorescence at room temperature. Finally, the attachment of a BODIPY chromophore to a cyclometalated Ir(III) metallic centre results in the achievement of efficient photosensitizers for singlet oxygen generation upon visible excitation light. Moreover, these hybrid compounds also show fluorescence emission, thus, they are interesting for bioimaging as well, and as a consequence, extensible to their use in theragnosis

The Exploration of Small Molecules, Lanthanide Complexes, and Catalysis using Electronic Structure Theory, Dynamics, and Machine Learning

With the ever increasing availability of computational resources, more challenging chemical systems can be studied. Among these challenges are the rotational and vibrational spectra of diatomic molecules within spectroscopic accuracy, the environmental perturbations induced on a rotating water molecule, the prediction of free binding energies of lanthanide complexes using machine learning, and the study of catalytic mechanisms through a theoretical framework. High levels of electronic structure theory were combined with a rigorous treatment of either the anharmonic vibrational wave functions to study diatomic molecules or the rotational wave functions to study H2O-pH2 interactions. The former was initially applied to the CF+ cation and excellent agreement was observed between theoretical and experimental spectroscopic constants. Likewise, the H2O-pH2 interactions were utilized to identify satellite peaks in the infrared spectra of a H2O-doped, pH2 crystal lattice. These peaks most likely occur due to a vacancy site directly around the H2O molecule. The study of lanthanide complexes is challenging due to their unique electronic structure. Specifically, the study of lanthanide-tris-β-diketone complexes was studied to calculate their respective free binding energies. Machine learning was utilized in this instance to act as the function which mapped the structure of the β-diketone ligands to the free binding energies. Predictions were made and several β-diketone ligands were identified which maximized the separation between lanthanide and lutetium. Finally, the study of catalytic mechanisms using theoretical methods is not without challenge due to the complex electronic structure of such systems. The hydrogen evolution reaction, the dehalogenation of CH2Cl2, the hydrogenation of small, unsaturated hydrocarbons, and the hydroformylation reaction were studied using either molecular electrocatalysts or transmetalated forms of the HKUST-1 metal-organic framework

Calculation of transition metal compounds using an extension of the CNDO formalism. II. Metal to metal bonding in binuclear transition metal compounds

A recently developed extension of the CNDO-method (Freund and Hohlneicher, 1979) is used to study the electronic structure of a no. of binuclear transition metal carbonyls and carboxylates with 4-fold or quasi-4-fold symmetry. The results are compared to those available from nonempirical calcns. Special attention is paid to the nature of the metal-metal bond. Connections with qual. MO-considerations allow a fairly general discussion of metal-metal bonding in binuclear transition metal complexes with basic 4-fold symmetry. A few, up to now unknown, but possibly existing, complexes are considered

Physical and electrochemical interactions within hybrid nanocomposites of ruthenium coordination complexes and single-walled carbon nanotubes

The research presented in this dissertation is a study of the interaction of ruthenium coordination complexes with single-walled carbon nanotubes (SWCNTs), a pursuit ultimately leading to the development of composite SWCNT materials. The work comprising this dissertation includes three major accomplishments: the synthesis and characterization of two new dinuclear ruthenium coordination complexes, the development of isothermal titration calorimetry (ITC) to thermodynamically quantify interactions with SWCNTs, and the fabrication and characterization of ruthenium complex--SWCNT hybrid nanocomposite electrodes. The work leading to these major accomplishments is inspired by the goal of attaining control over assembly of nanoscale building blocks, i.e. SWCNTs. The first step towards this goal is the development of appropriate molecules that can nondestructively link two SWCNTs together without damaging the physical structure of the tube. [Cl(trpy)Ru(tpphz)Ru(trpy)Cl](PF6) 2 and [(phen)2Ru(tpphz)Ru(trpy)Cl](PF6)3 are the two ruthenium dimer molecules synthesized and discussed herein. They possess a rigid nanoscale pocket that contains conjugated p-electron density capable of interacting with the walls of SWCNTs. During the work to synthesize these complexes significant improvements were made to synthetic procedures to produce important precursors. The synthesis of the two complexes and the new synthetic procedures were novel. The second step required the development of a new tool (ITC) to study the interaction thermodynamics of dispersions of SWCNTs. ITC is a well established tool to measure binding thermodynamics of biological proteins and enzymes. Based on the analogy that can drawn between SWCNTs in solution and proteins, I developed ITC methods and protocols for measuring interactions of solvents with SWCNTs as well as the binding of the ruthenium dimer complexes with SWCNTs. I have established that ITC can be an important nanoscale science and materials development tool which can provide detailed insight into the thermodynamic interactions of nanomaterials in solution. I combined SWCNTs and ruthenium complexes, and developed procedures to fabricate nanocomposite films. The films produced by our method improve on previously reported techniques by avoiding surfactants and binders which retard the properties of SWCNT films. I was able to transfer these films to various substrates and they were shown to have enhanced capacitance versus pristine SWCNT films when used as an electrode in an electrochemical cell. Augmenting SWCNT electrodes in this way has not been reported and the technique is a promising vehicle for photo-induced charge transfer as well as cheaper and lighter capacitor devices

The Critical Role of Mechanism-Based Models for Understanding and Predicting Liposomal Drug Loading, Binding and Release Kinetics

Liposomal delivery systems hold considerable promise for improvement of cancer therapy provided that critical formulation design criteria can be met. The main objective of the current project was to enable quality by design in the formulation of liposomal delivery systems by developing comprehensive, mechanism-based mathematical models of drug loading, binding and release kinetics that take into account not only the therapeutic requirement but the physicochemical properties of the drug, the bilayer membrane, and the intraliposomal microenvironment. Membrane binding of the drug affects both drug loading and release from liposomes. The influence of bilayer composition and phase structure on the partitioning behavior of a model non-polar drug, dexamethasone, and its water soluble prodrug, dexamethasone phosphate, was evaluated. Consequently, a quantitative dependence of the partition coefficient on the free surface area of the bilayer, a property related to acyl chain ordering, was noted. The efficacy of liposomal formulations is critically dependent on the drug release rates from liposomes. However, various formulation efforts to design optimal release rates are futile without a validated characterization method. The pitfalls of the commonly used dynamic dialysis method for determination of apparent release kinetics from nanoparticles were highlighted along with the experimental and mathematical approaches to overcome them. The value of using mechanism-based models to obtain the actual rate constant for nanoparticle release was demonstrated. A novel method to improve liposomal loading of poorly soluble ionizable drugs using supersaturated drug solutions was developed using the model drug AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), a poorly soluble camptothecin analogue. Enhanced loading with a drug to lipid ratio of 0.17 was achieved and the rate and extent of loading was explained by a mathematical model that took into account the chemical equilibria inside and outside the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Tunable liposomal release kinetics would be highly desirable to meet the varying therapeutic requirements. A large range of liposome release half-lives from 1 hr to 892 hr were obtained by modulation of intraliposomal pH and lipid composition using dexamethasone phosphate as a model ionizable drug. The mathematical models developed were successful in accounting for the change in apparent permeability with change in intraliposomal pH and bilayer free surface area. This work demonstrates the critical role of mechanism-based models in design of liposomal formulations