Doctor of Philosophy / Department of Chemistry / Paul E. Smith / In the past several decades, molecular dynamics (MD) simulations have played an important role in providing atomic details for phenomena of interest. The force field used in MD simulations is a critical factor determining the quality of the simulations. Kirkwood-Buff (KB) theory has been applied to study preferential interactions and to develop a new force field. KB theory provides a path from quantities determined from simulation data to the corresponding thermodynamic data. Here we combine KB theory and molecular simulations to study a variety of intermolecular interactions in solution. First, a force field for the computer simulation of aqueous solutions of alcohols is presented. The force field is designed to reproduce the experimentally observed density and KB integrals for a series of alcohols, allowing for an accurate description of alcohols’ activity. Other properties such as the translational diffusion constant and heat of mixing are also well reproduced. Second, the newly developed force field is then extended to more complicated systems, such as peptide or mini-proteins, to determine backbone dihedral potentials energetics. The models developed here provide a basis for an accurate force field for peptides and proteins. Third, we have then studied the surface tension of a variety water models. Results showed that different simulation conditions can affect the final values of surface tension. Finally, by using the Kirkwood-Buff theory of solution and surface probability distributions, we attempted to characterize the properties of the Gas/Liquid interface region. The same approach is then used to understand the relationship between changes in surface tension, the degree of surface adsorption or depletion, and the bulk solution properties.

Doctor of Philosophy / Department of Chemistry / Paul Edward Smith / The activity and function of many macromolecules in cellular environments are coupled with the binding of ions such as alkaline earth metal ions and poly oxo anions. These ions are involved in the regulation of important processes such as protein crystallization, nucleic acid and protein stability, enzyme activity, and many others. The exact mechanism of ion specificity is still elusive. In principle, computer simulations can be used to help provide a molecular level understanding of the dynamics of hydrated ions and their interactions with the biomolecules. However, most of the force fields available today often fail to accurately reproduce the properties of ions in aqueous environments. Here we develop a classical non polarizable force field for aqueous alkaline earth metal halides (MX₂) where M = Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺ and X = Cl⁻, Br⁻, I⁻, and for some biologically important oxo anions which are NO₃⁻, ClO₄⁻, H₂PO₄⁻ and SO₄²⁻, for use in biomolecular simulations. The new force field parameters are developed to reproduce the experimental Kirkwood-Buff integrals. The Kirkwood-Buff integrals can be used to quantify the affinity between molecular species in solution. This helps to capture the fine balance between the interactions of ions and water. Since this new force field can reproduce the experimental Kirkwood-Buff integrals for most concentrations of the respective salts, they are capable of reproduce the experimental activity derivatives, partial molar volumes, and excess coordination numbers. Use of these new models in MD simulations also leads to reasonable diffusion constants and dielectric decrements. Attempts to develop force field parameters for CO₃²⁻, HPO₄²⁻ and PO₄³⁻ ions were unsuccessful due to an excessive aggregation behavior in the simulations. Therefore, in an effort to overcome this aggregation behavior in the simulations, we have investigated scaling the anion to water interaction strength, and also the possibility of using a high frequency permittivity in the simulations. The strategy of increasing relative permittivity of the system to mimic electronic screening effects are particularly promising for decreasing the excessive ion clustering observed in the MD simulations.

Doctor of Philosophy / Department of Chemistry / Paul E. Smith / The Kirkwood-Buff (KB) theory of solutions, published in 1951, established a route from integrals over radial (pair) distribution functions (RDFs) in the grand canonical ensemble to a set of thermodynamic quantities in an equivalent closed ensemble. These “KB integrals” (KBIs) can also be expressed in terms of the particle-particle (i.e., concentration or density) fluctuations within grand canonical ensemble regions. Contributions by Ben-Naim in 1977 provided the means to obtain the KBIs if one already knew the set of thermodynamic quantities for the mixture of interest; that is, he provided the inversion procedure. Thus, KB theory provides a two-way bridge between local (microscopic) and global (bulk/thermodynamic) properties. Due to its lack of approximations, its wide ranging applicability, and the absence of a competitive theory for rigorously understanding liquid mixtures, it has been used to understand solution microheterogeneity, solute solubility, cosolvent effects on biomolecules, preferential solvation, etc. Here, after using KB theory to test the accuracy of pair potentials, we present and illustrate two extensions of the theory, resulting in a general Fluctuation Solution Theory (FST). First, we generalize KB theory to include two-way relationships between the grand canonical ensemble’s particle-energy and energy-energy fluctuations and additional thermodynamic quantities. This extension allows for non-isothermal conditions to be considered, unlike traditional KB theory. We illustrate these new relationships using analyses of experimental data and molecular dynamics (MD) simulations for pure liquids and binary mixtures. Furthermore, we use it to obtain conformation-specific infinitely dilute partial molar volumes and compressibilities for proteins (other properties will follow) from MD simulations and compare the method to a non-FST method for obtaining the same properties. The second extension of KB theory involves moving beyond doublet particle fluctuations to additionally consider triplet and quadruplet particle fluctuations, which are related to derivatives of the thermodynamic properties involved in regular KB theory. We present these higher order fluctuations obtained from experiment and simulation for pure liquids and binary mixtures. Using the newfound experimental third and fourth cumulants of the distribution of particles in solution, which can be extracted from bulk thermodynamic data using this extension, we also probe particle distributions’ non-Gaussian nature.

A technology for optimization of potential parameters from condensed phase simulations (POP) is discussed and illustrated. It is based on direct calculations of the derivatives of macroscopic observables with respect to the potential parameters. The derivatives are used in a local minimization scheme, comparing simulated and experimental data. In particular, we show that the Newton Trust-Region protocol allows for accurate and robust optimization. POP is illustrated for a toy problem of alanine dipeptide and is applied to folding of the peptide WAAAH. The helix fraction is highly sensitive to the potential parameters while the slope of the melting curve is not. The sensitivity variations make it difficult to satisfy both observations simultaneously. We conjecture that there is no set of parameters that reproduces experimental melting curves of short peptides that are modeled with the usual functional form of a force field. We then apply the newly developed technology to study the liquid mixture of tert-butanol and water. We are able to obtain, after 4 iterations, the correct phase behavior and accurately predict the value of the Kirkwood Buff (KB) integrals. We further illustrate that a potential that is determined solely by KB information, or the pair correlation function, is not necessarily unique. / text

It has long been observed that salts affect proteins in a variety of ways, yet comprehensive explanations for different salt effects are still lacking. In the work presented here, the effect of salts on proteins has been investigated through three different effects: the hydrophobic effect; their conformational stability; the hydrogen bonding network of water in a protein’s hydration shell. UV-vis absorbance and fluorescence spectroscopy were used to monitor changes in two model systems, the phenol-acetate contact pair and the model enzyme ribonuclease t1. It was shown that salts affect the hydrophobicity of the contact pair according to their charge density, induced image charges play an important role in the observed salt-induced increase of ribonuclease t1 stability, and that salts affect ribonuclease t1 activity through modulation of the hydrogen bonds of water in the enzyme’s hydration shell. This work contributes a greater understanding of the effect of salts on proteins.

It has long been observed that salts affect proteins in a variety of ways, yet comprehensive explanations for different salt effects are still lacking. In the work presented here, the effect of salts on proteins has been investigated through three different effects: the hydrophobic effect; their conformational stability; the hydrogen bonding network of water in a protein’s hydration shell. UV-vis absorbance and fluorescence spectroscopy were used to monitor changes in two model systems, the phenol-acetate contact pair and the model enzyme ribonuclease t1. It was shown that salts affect the hydrophobicity of the contact pair according to their charge density, induced image charges play an important role in the observed salt-induced increase of ribonuclease t1 stability, and that salts affect ribonuclease t1 activity through modulation of the hydrogen bonds of water in the enzyme’s hydration shell. This work contributes a greater understanding of the effect of salts on proteins.

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Thesis (MA)--University of Stellenbosch, 2005. / This study concerns the genre analysis of five texts (articles) in isiXhosa from Bona Magazine using genre theoretic approach. / ENGLISH ABSTRACT: This study concerns the genre analysis of five texts (articles) in isiXhosa from Bona Magazine using genre theoretic approach. They all analyse genre of social community leaders using the theory of Grabe & Kaplan. (1996) All five articles re attached as appendices at the end of this assignment. The chapters 2 and 3 present an overview of different views expressed by different linguistics and researchers in relation to the genre theoretic approach and how these theories are applied in analyses. The views of Bhatia (1993) are also used in that he promotes the use of language in text when people communicate either in written or verbal format. Bhatia emphasizes the use of text linguistic properties and insights in the culture of participants to ensure that communication purpose is reached. Among other things, he invokes text structure, lexical choices, cohesion and coherence of text, content and theme are analyzed. This study investigates the social cognitive and linguistic choices and how they influence writing and reading. The purpose and meaning of the text is depicted as very important in the analysis of written text. (Bhatia; 1993) The first part of chapter 4 deals with the theory of Grabe & Kaplan (1996), which emphasizes the use of ethnography of writing. The ethnography of writing according to Grabe & Kaplan (1996) entails the answers to the following basic questions: Who is writing? To whom? For what purpose? Why? When? And how? The answers to these questions are to be formed in the analysis of the articles on Grabe & Kaplan's views on the relationship between ethnography of writing and lexicon of writing skills are also analyzed. The study also includes Halliday's (1984) views. Educating children in their home language environment makes them to learn better as they write in their own language and about the things they know. Lastly there is a short discussion about the relationship between the new genre approach and Outcomes-Based Education. (OBE) The similarities they share in connection with aims, goals and purposes as language teaching approached are touched upon. / AFRIKAANSE OPSOMMING: Hierdie studie hou verband met die genre analise van vyf tekste (artikels) in Xhosa uit die Bona tydskrif. Die analises handel oor die genre van sosiale gemeenskapsleiers binne die raamwerk van Grabe en Kaplan (1996). AI vyf die artikels is in In Appendix aangeheg aan die einde van hierdie werkstuk. Hoofstukke 2 en 3 bied In oorsig aan van verskillende sieninge van linguiste t.o.v. die genre-teoretiese benadering en die aanwending van die teoretiese uitgangspunte in analises van tekste. Die sieninge van Bhatia (1993) word ook ingespan m.b.t. die kommunikasie tussen mense. Bhatia wend tekslinguistiese eienskappe aan asook sosiale en kulturele insigte in die ondersoek van hoe kommunikatiewe doelstelling bereik word. Hy gebruik o.a. tekslinguistiese kenmerke, leksikale keuses, kohesie en koherensie, en tematiese realiserings in die teks. Die doelstelling van die teks is uiters belangrik volgens die betekenis wat Bhatia in die teks ondersoek. Die eerste gedeelte van hoofstuk 4 handel oor Grabe en Kaplan (1996) se model van tekskonstruksie en die etnografie van skryf. Die onderrig van leerders is beter as hulle in hulle huistaal skryf en leer. Die studie beskou die onderliggende uitgangspunte van Kurrikulum 2005 m.b.t. die genre benadering tot die onderrig van Xhosa / ISICATSHULWA Olu fundo luphanda ngohlalutyo ngohlobo Iwejenri kumabali esiXhosa afumaneka kwimagazini iBona kusetyenziswa ulwimi IwesiXhosa. La ngamabali amahlanu angeenkokheli zoluntu, nazakuhlalutywa ngokweembono zikaGrabe noKaplan (1996). Kuqalwe ngokushwankathela iinkcazo zohlobo Iwejenri, neembono zabaphononongi neengcali ezahlukeneyo malunga nolu hlobo lutsha lokuhlalutya. Kucaciswa imbono kaBhatia (1993) mlunga nokuphononongwa kwendlela yokusetyenziswa kolwimi xa kunxityelelwana, kwiitekisi ezithethwayo nezibhaliweyo. Oku kucaciswa ngokupheleleyo xa kuhlalutywa la mabali mahlanu angenkokheli zolunu. Phakathi kwezinto ezijongwayo xa kuhlalutywa nobhalo Iwamabali; lulwakhiwo Iweetekisi, ngumxholo, lukhetho Iwamagama, lunamathelwano nonxulumano. Kwakhona indlela umbhali ayiphuhlisa ngayo intsingiselo yetekisi yakhe ukuze injongo yakhe izaliseke. Indlela ezisetyenziswa ngayo iimpawu eziziparametha eziyimbono ka Grabe noKaplan (1996) xa kuhlalutywa la mabali angenkokheli zoluntu. Xa kuthethwa ngezi mpawu, kuxelwa ukuphendulwa kwemibuzo yobhalo ethi; ngubani umbhali? Ubhala ntoni? Ubhalela bani? Yintoni injongo yakhe? Kutheni ebhala nje? Ezi mpawu azaneli knceda umbhali ukuba abhale kakuhle koko zinceda nomfundi ukuba ahlalutye kakhuhle okubhaliweyo. Kwakhona imbono kaHaliday ethi xa kusetyenziswa ulwimi makusetyenziswe izinto nemizekelo engentlalo nenkcubeko yabantu. Lilonke yena ugxininisa ukufakwa kwenkcubeko kwimfundo yabantwana. Uyixhasa lembono yakhe ngokuthi abafundi baqonda lula xa befunda ngolwimi Iwabo nange nkcubeko yabo nangezinto ezibangqongileyo. Le mbono iyahambelana nokufundisa ngohlobo Iwejenri yona imkhululayo umntwana ukuba azifundele ngokwengqondo angadityaniswa nomnye. Kwakhona kolu fundo kuthelekiswe uhlobo Iwejenri nohlobo olusetyenziswayo kwizikolo zethu olujonge iziphumo uhlobo Iwe O. B. E. Kujongwa nendlela ezinxulumene ngayo, ngenxa yokufana kweenjongo zazo kwaneziphumo kubantwana abafundiswayo kusetyenziswa zona.

It is a central claim of modern linguistic theory that linguists do not prescribe, but describe language as it is, without pronouncing on correctness or judging one variety better than another. This attempt to exclude evaluation is motivated by a desire to be ' politically correct', which hinders objective analysis of language, and by an ill-advised imitation of the natural sciences, which obstructs the discipline's progress towards becoming a science in its own right. It involves linguists, as users of a valued variety, in self-deception and disingenuousness, distances them from the concerns of the ordinary language user, and betrays a failure to understand the involvement of social values in language, the nature of language itself, and the limits of linguistic science. On a wider scale, linguistics reflects society's devaluing and mechanisation of language. Despite growing concern expressed in the literature, and the incoherence that becomes apparent when linguists attempt to address social problems using a theory that regards language as an autonomous object, newcomers to the discipline continue to be taught that anti-prescriptivism is the natural corollary of a scientific approach to language. This thesis suggests that the way out of these difficulties is to rethink the meaning of ' theory' in linguistics. If we take the reflexivity of language seriously, building on M.A.K. Halliday's notion of 'linguistics as metaphor', we are reminded that a linguistic theory is made of language. Metalanguage must use the experiential and interpersonal meaning-making resources of everyday language. It follows that a linguistic theory cannot escape being evaluative, because evaluation is an inherent part of interpersonal meaning. If we fail to notice our own metalinguistic evaluation, this is because language disguises its evaluative meanings, or perhaps we are just not used to thinking of them as part of the grammar. To achieve clarity about the involvement of value in language, we need to turn our metalanguage back on itself - 'using the grammar to think with about the grammar' . Some ways of doing this are demonstrated here, turning the resources of systemic functional linguistics on linguists' own language. The circularity of this process should be seen not as a drawback but as a salutary reminder that linguistics is an interpretive rather than a discovery process. This knowledge should help us revalue language and make a place for evaluation in linguistic theory, paving the way for a socially responsible and productive linguistics.