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    On the origin of optical rotation changes during the κ-carrageenan disorder-to-order transition
    (Elsevier Ltd., 2024-06-01) Westberry BP; Rio M; Waterland MR; Williams MAK
    It is well established that solutions of both polymeric and oligomeric κ-carrageenan exhibit a clear change in optical rotation (OR), in concert with gel-formation for polymeric samples, as the solution is cooled in the presence of certain ions. The canonical interpretation - that this OR change reflects a 'coil-to-helix transition' in single chains - has seemed unambiguous; the solution- or 'disordered'-state structure has ubiquitously been assumed to be a 'random coil', and the helical nature of carrageenan in the solid-state was settled in the 1970s. However, recent work has found that κ-carrageenan contains substantial helical secondary structure elements in the disordered-state, raising doubts over the validity of this interpretation. To investigate the origins of the OR, density-functional theory calculations were conducted using atomic models of κ-carrageenan oligomers. Changes were found to occur in the predicted OR owing purely to dimerization of chains, and - together with the additional effects of slight changes in conformation that occur when separated helical chains form double-helices - the predicted OR changes are qualitatively consistent with experimental results. These findings contribute to a growing body of evidence that the carrageenan 'disorder-to-order' transition is a cooperative process, and have further implications for the interpretation of OR changes demonstrated by macromolecules in general.
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    Molecular dynamics simulation of inter-molecular interactions : a thesis submitted to Massey University in Albany, Auckland in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Computational Biochemistry
    (Massey University, 2019) Shadfar, Shamim Zahra
    Many aspects of the operation of chemical and biological systems are based on intermolecular interactions. In this work, binding modes and interactions between molecules at a range of scales have been studied, using molecular dynamics (MD) simulations. The first chapter provides an introduction of each of the different chemical and biological systems that are studied in this work. It also introduces MD and its role in the context of this research. The second chapter corresponds to the study of host-guest interactions for cyclodextrin- bullvalene complexes. Bullvalene is a shapeshifter molecule, which interconverts between different isomers at room temperature. The goal of this chapter is to capture one favourable isomer of bullvalene (guest molecule) by binding it to cyclodextrin as a host molecule. This chapter consists of two smaller chapters (2i and 2ii). The former details the development and validation of a “host-guest binding potential energy profiling” (HGBPEP) method, which is a rotational interaction energy screening method designed for prediction of the most favourable orientation and position of bullvalene isomers with respect to cyclodextrin. The latter investigates the interaction of bullvalene isomers and cyclodextrin molecules, and finally binding free energy values of the complexes are calculated. The third chapter describes KstR, a transcriptional repressor in Mycobacteria. KstR is required for Mycobacterium tuberculosis (Mtb) pathogenesis as well as regulating the initial steps in cholesterol degradation by controlling the expression of the enzymes that carry out the early stages of cholesterol catabolism. Therefore, this protein is of great interest for development of new tuberculosis treatments. In this chapter, the stability and conformational changes of KstR in its different states – apo, DNA-bound and ligand-bound –have been studied. The main goal is to investigate the binding mechanism of KstR to DNA, as well as the effect of DNA and ligand binding on the structure and dynamics of KstR more generally, using MD simulations. In the fourth chapter, KstR2, another Mtb transcriptional repressor, is studied. KstR2 represses a 14-gene regulon involved in the later steps of cholesterol degradation. It is structurally similar to KstR, but has been proposed to act through a novel scissor-like mechanism. This chapter investigates two key questions regarding the mechanism of action of KstR2: first, the effect of mutating the key switch residue ARG170 to ALA, and second, the effect of ligand binding on its structure and motion. The focus of the fifth and final chapter is phosphatidylinositide 3-kinases (PI3Ks), which are proteins that take part in signalling pathways regulating factors like cell growth, survival and proliferation, which in turn are involved in cancer. The interaction between PI3Kα and another protein, RAS, is very important in the formation, growth and maintenance of RAS- driven tumours. A model of PI3Kα (class IA PI3K) has therefore been built, as well as of RAS associated with a model cell membrane, and MD simulations used to investigate the process by which the two proteins interact with one another and with the lipid bilayer. Altogether, this thesis uses MD simulations to provide insight into intermolecular interactions at a range of scales, with a particular focus on proteins involved in tuberculosis and in cancer.
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    Charged polysaccharides as model polyelectrolytes : computational studies of transport and conformational properties : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Physics at Massey University, Palmerston North, New Zealand
    (Massey University, 2018) Irani, Amir Hossein
    Homogalacturonans (HGs) are polysaccharide co-polymers of galacturonic acid and its methylesterified counterpart, that play a crucial role in the mechanobiology of the cell walls of all land plants. When extracted, in solution, at pH values above the pKa, the carboxyl groups carried by the unmethylesterified residues endow the polymer chains with charge, making these systems interesting polyelectrolytes. The inter- and intra-molecular distributions of the non-charged methylesterified residues and their charged methylesterified counterparts are vital behaviour-determining characteristics of a sample's structure. Previous work has led to the development of techniques for the control of the amount and distribution of charges, and with these tools and samples available in different degrees of polymerisation, including small oligomers, the system offers a flexible test-bed for studying the behaviour of biological polyelectrolytes. This thesis is rooted in exploring the use of computational approaches, in particular molecular dynamics, to calculate the conformation of such polyelectrolytes in solution and to describe their transport properties in electric fields. The results of simulations are, in all cases, compared with the results of experimental work in order to ground the simulations. First, in chapter 2, these simulations are applied to calculate the free solution electrophoretic mobilities of galacturonides, charged oligosaccharides derived from digests of partially methylesterified HGs. The simulations are compared with experiment and were found to correctly predict the loss of resolution of electrophoretic mobilities for fully-charged species above a critical degree of polymerisation (DP), and the ionic strength dependence of the electrophoretic mobilities of different partially charged oligosaccharides. Next, in chapter 3, molecular dynamics (MD) simulations are used to calculate the electrophoretic mobilities of HGs that have different amounts and distributions of charges placed along the backbone. The simulations are shown to capture experimental results well even for samples that possess high charge densities. In addition they illuminate the role that local counterion condensation can play in the determination of the electrophoretic mobility of heterogeneous blocky polyelectrolytes that cannot be adequately described by a single chain-averaged charge spacing. Finally, in chapter 4, the last part of the research focusses on the configurations of these polyelelectrolytes in dilute solution, and on how the interactions between several chains can lead to the spatially heterogenous nature of polyelectrolyte solutions. Such questions are of long standing interest in the polyelectrolyte field and the results are compared with results from Small Angle X-Ray Scattering(SAXS). Overall the work demonstrates how state of the art MD approaches can provide insights into experimental results obtained from fundamentally interesting and biologically relevant polyelectrolytes.
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    On using automated algorithms to parameterise molecules for molecular dynamics simulations and investigating suitable ensembles for the simulation of naphthalimide monolayers : a thesis submitted to Massey University in Albany, Auckland in fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry, Massey University, Auckland
    (Massey University, 2017) Welsh, Ivan
    Molecular dynamics simulations provide a means to investigate the spatial and temporal evolution of systems of molecules at atomic resolution. Force fields are used to describe the interactions between atoms contained within the system. A number of such force fields have been developed over the years, with a focus on force fields for use in simulations of biochemical systems, in particular, protein systems. This thesis is primarily focused on extending the range of systems that can be simulated through providing means for automated generation of force field parameters for large novel molecules. One component of existing force fields that is generally poorly parameterised are the dihedral terms. In combination with the non-bonded terms, the dihedral terms are used to describe the rotational energy profile about bonds, and have a large influence on the conformational properties of a simulated system. A new method for the determination of dihedral parameters is developed, utilising high level quantum mechanical calculations. With the use of local elevation molecular dynamics simulations, this method is applied to the case of protein backbone dihedrals within the GROMOS force field. When one desires to simulate the interaction of a novel molecule with some biochemical system, the novel molecule must be parameterised in a manner that is compatible with the force field used to describe the biochemical system. However, doing so is a slow, tedious, and error prone process, especially when the novel molecule is large. To combat this, a new algorithm, known as CherryPicker, was developed. CherryPicker is a graph based algorithm which enables rapid parameterisation of large molecules through fragment comparison with a library of previously parameterised small molecules. The algorithm design is discussed and tested on a few simple test cases in part II. Part III steps away from the parameterisation focus of this thesis and looks at the simulation of naphthalimide monolayers. Naphthalimides have applications in sensing environments as they have absorption and fluorescence emission spectra lying within the UV and visible regions of light. With a long chain alkane substituted at the N-imide site, they become amphiphilic and can form monolayers on the surface of water, and can be transferred to a solid substrate when at a desired compression level. Molecular dynamics simulations can be used to provide insight into the formation of compressed monolayer phase. Here, the effect of different ensembles, namely NVT, NPT, and NgT are investigated for use in simulating a naphthalimide monolayer.
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    Molecular diffusion as measured by pulsed field gradient nuclear magnetic resonance : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Chemistry at Massey University
    (Massey University, 1982) Kissock, Jeremy Samuel Druce
    The work presented in this thesis may be conveniently divided into three sections. Firstly the development of a Carr-Purcell-Meiboom-Gill pulse sequence for use in the pulsed field gradient experiment in order to examine diffusion over long diffusion times is described. Secondly diffusion coefficients of both components of binary mixtures of methanol and benzene have been measured using pulsed field gradient fourier transform NMR. Results showed self-association to be dominant over AB association and a brief qualitative explanation of the reasons for this is given. In the third section, which is the major part of this thesis, diffusion coefficients of water in the caesium perfluoro-octanoate, water system have been determined at various weight fractions and temperatures by pulsed field gradient NMR. The liquid crystalline phases occuring within the system are the isotropic micellar solution, the nematic amphiphilic mesophase and the smetic lamellar mesophase. Water was found to pass through the system in an unrestricted and virtually unhindered manner. These results were discussed in terms of the known structures of the phases and with respect to possible permeation mechanisms. No definite conclusion as to the permeation mechanism is possible. The limitations in the use of surfactants as membrane models is discussed.
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    Molecular dynamics modelling of biomolecular interactions with lipid membranes and novel coarse grain lipid model development : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Albany, New Zealand
    (Massey University, 2017) Kobzev, Elisey
    Lipids comprise a key component of the cellular membrane and are essential to many biological processes. In silico investigations provide valuable opportunities to study the dynamics and structure of biological molecules, such as lipid membranes and the molecules that interact with them, at near atomic resolutions. In the context of this thesis three research projects were undertaken with a focus on lipid membrane simulations. The structure and dynamics of the novel antibacterial battacin analogue peptides and their interactions with model membranes of the common pathogenic gram positive and gram negative bacterial species Staphylococcus aureus and Escherichia coli were studied. Antibacterial peptides are a key area of research due to their potential medicinal applications in overcoming the current antibiotic resistance crisis. However, detailed knowledge of their mode of action is often lacking. The peptides were to found to insert into the bacterial membranes, facilitated by the insertion of the fatty acid moiety, and showed strong affinity for all three types of membranes studied. Antifreeze protein 1 (AFP1) is critical to cell survival at near freezing temperatures. Structural analysis of the behavior of AFP1 is presented, including a study of its possible aggregation. Interactions of AFP1 were studied in conjunction with a model of a typical cell membrane. AFP1 units were found to be flexible in solution, adopting a variety of non α-helical structures. In certain cases, two AFP1 proteins aggregated together and interacted with each other. Furthermore, AFP1 interacted with the unsaturated lipid membrane, coming to rest on its surface, providing insight into the freezing damage prevention mechanism. Finally, in order to facilitate simulation of larger biological membrane systems, a novel supra-atomic phospholipid model was proposed, and model parameters developed for the common lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). The model is based on and ultimately compatible with the GROMOS 54a8 atomic-level force field103 including the GROMOS coarse-grained water model111. It is also polarisable, unlike many popular supra-atomic models. The DPPC model was developed following a bottom-up approach, and is intended to pave a way for stepwise parameterisation of other lipids, to build a library of “plug and play” lipid parameters.
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    Graph theoretic and electronic properties of fullerenes, &, Biasing molecular modelling simulations with experimental residual dipolar couplings : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University, Albany, New Zealand
    (Massey University, 2015) Wirz, Lukas N
    In this thesis two different models, that is levels of abstraction, are used to explore specific classes of molecular structures and their properties. In part I, fullerenes and other all-carbon cages are investigated using graphs as a representation of their molecular structure. By this means the large isomer space, simple molecular properties as well as pure graph theoretical aspects of the underlying graphs are explored. Although chemical graphs are used to represent other classes of molecules, cavernous carbon molecules are particularly well suited for this level of abstraction due to their large number of isomers with only one atom type and uniform hybridisation throughout the molecule. In part II, a force field for molecular dynamics, that is the step wise propagation of a molecular structure in time using Newtonian mechanics, is complemented by an additional term that takes into account residual dipolar couplings that are experimentally measured in NMR experiments. Adding this force term leads to more accurate simulated dynamics which is especially important for proteins whose functionality in many cases crucially depends on their dynamics. Large biomolecules are an example of chemical systems that are too large for treatment with quantum chemical methods but at the same time have an electronic structure that is simple enough for accurate simulations with a forcefield.
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    Effect on the mechanical properties of type I collagen of intra-molecular lysine-arginine derived advanced glycation end-product cross-linking
    (Elsevier, 28/11/2017) Collier TA; Nash A; Birch HL; de Leeuw NH
    Non-enzymatic advanced glycation end product (AGE) cross-linking of collagen molecules has been hypothesised to result in significant changes to the mechanical properties of the connective tissues within the body, potentially resulting in a number of age related diseases. We have investigated the effect of two of these cross-links, glucosepane and DOGDIC, on the tensile and lateral moduli of the collagen molecule through the use of a steered molecular dynamics approach, using previously identified preferential formation sites for intra-molecular cross-links. Our results show that the presence of intra-molecular AGE cross-links increases the tensile and lateral Young’s moduli in the low strain domain by between 3.0 - 8.5 % and 2.9 - 60.3 % respectively, with little effect exhibited at higher strains.