OpenUCT :: Browsing by Author "Naidoo, Kevin J"

Browsing by Author "Naidoo, Kevin J"

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Open Access
A comparative study between the cubic spline and b-spline interpolation methods in free energy calculations
(2020) Kaya, Hikmet Emre; Naidoo, Kevin J
Numerical methods are essential in computational science, as analytic calculations for large datasets are impractical. Using numerical methods, one can approximate the problem to solve it with basic arithmetic operations. Interpolation is a commonly-used method, inter alia, constructing the value of new data points within an interval of known data points. Furthermore, polynomial interpolation with a sufficiently high degree can make the data set differentiable. One consequence of using high-degree polynomials is the oscillatory behaviour towards the endpoints, also known as Runge's Phenomenon. Spline interpolation overcomes this obstacle by connecting the data points in a piecewise fashion. However, its complex formulation requires nested iterations in higher dimensions, which is time-consuming. In addition, the calculations have to be repeated for computing each partial derivative at the data point, leading to further slowdown. The B-spline interpolation is an alternative representation of the cubic spline method, where a spline interpolation at a point could be expressed as the linear combination of piecewise basis functions. It was proposed that implementing this new formulation can accelerate many scientific computing operations involving interpolation. Nevertheless, there is a lack of detailed comparison to back up this hypothesis, especially when it comes to computing the partial derivatives. Among many scientific research fields, free energy calculations particularly stand out for their use of interpolation methods. Numerical interpolation was implemented in free energy methods for many purposes, from calculating intermediate energy states to deriving forces from free energy surfaces. The results of these calculations can provide insight into reaction mechanisms and their thermodynamic properties. The free energy methods include biased flat histogram methods, which are especially promising due to their ability to accurately construct free energy profiles at the rarely-visited regions of reaction spaces. Free Energies from Adaptive Reaction Coordinates (FEARCF) that was developed by Professor Kevin J. Naidoo has many advantages over the other flat histogram methods. iii Because of its treatment of the atoms in reactions, FEARCF makes it easier to apply interpolation methods. It implements cubic spline interpolation to derive biasing forces from the free energy surface, driving the reaction towards regions with higher energy. A major drawback of the method is the slowdown experienced in higher dimensions due to the complicated nature of the cubic spline routine. If the routine is replaced by a more straightforward B-spline interpolation, sampling and generating free energy surfaces can be accelerated. The dissertation aims to perform a comparative study between the cubic spline interpolation and B-spline interpolation methods. At first, data sets of analytic functions were used instead of numerical data to compare the accuracy and compute the percentage errors of both methods by taking the functions themselves as reference. These functions were used to evaluate the performances of the two methods at the endpoints, inflections points and regions with a steep gradient. Both interpolation methods generated identically approximated values with a percentage error below the threshold of 1%, although they both performed poorly at the endpoints and the points of inflection. Increasing the number of interpolation knots reduced the errors, however, it caused overfitting in the other regions. Although significant speed-up was not observed in the univariate interpolation, cubic spline suffered from a drastic slowdown in higher dimensions with up to 103 in 3D and 105 in 4D interpolations. The same results applied to the classical molecular dynamics simulations with FEARCF with a speed-up of up to 103 when B-spline interpolation was implemented. To conclude, the B-spline interpolation method can enhance the efficiency of the free energy calculations where cubic spline interpolation has been the currently-used method.
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Acceleration of the GAMESS-UK electronic structure package on graphical processing units
(Wiley, 2011) Wilkinson, Karl A; Sherwood, Paul; Guest, Martyn F; Naidoo, Kevin J
The approach used to calculate the two-electron integral by many electronic structure packages including generalized atomic and molecular electronic structure system-UK has been designed for CPU-based compute units. We redesigned the two-electron compute algorithm for acceleration on a graphical processing unit (GPU). We report the acceleration strategy and illustrate it on the (ss|ss) type integrals. This strategy is general for Fortran-based codes and uses the Accelerator compiler from Portland Group International and GPU-based accelerators from Nvidia. The evaluation of (ss|ss) type integrals within calculations using Hartree Fock ab initio methods and density functional theory are accelerated by single and quad GPU hardware systems by factors of 43 and 153, respectively. The overall speedup for a single self consistent field cycle is at least a factor of eight times faster on a single GPU compared with that of a single CPU.
Open Access
A computational and synthetic study of poly(benzyl phenyl ether) dendrimers
(1998) Hughes, Samantha Jayne; Moss, John R; Naidoo, Kevin J
Organic and organochromium poly(benzyl phenyl ether) dendrimers have been investigated by synthetic · and computational methods. The first generation organic benzyl alcohol and bromide wedges have been prepared, and a first generation organic dendrimer was synthesised. The preparation of novel organochromium dendrimers has been investigated. Several chromium arene complexes were prepared by different routes, and the halogenation methodology was thoroughly explored with various reagents. The target compound, a chromium complexed first generation dendritic wedge, was not accessible by any of the methods investigated. The novel compound (dibenzyl ether)bis[tricarbonylchromium(O)] has been prepared by two routes and the crystal structure of this complex was determined. Several other chromium arene complexes were synthesised, and the crystal structure of one of these, (benzyl methyl ether)tricarbonylchromium(O), was determined. The structure and properties of the organic and organochromium dendrimers have been investigated by molecular mechanics and molecular dynamics techniques. The existing CHARMm polymer force field was extended to include parameters for the tricarbonylchromium moiety. The two crystal structures solved as part of the synthetic effort, were used in this regard. The accuracy of the new parameters was assessed by simulation of the crystal structure of ( dibenzyl ether)bis[tricarbonylchromium(O)]. The important ether linkage torsion angle parameter, which plays a significant role in the topology of the dendrimer, was singled out for refinement. The torsion angle was parameterised with the model compound benzyl phenyl ether, by fitting the CHARMm results for rotation about the dihedral, to ab initio torsional data. Molecular dynamics simulations have been performed on generations one through five of the organic and organochromium dendrimers. The radius of gyration and RMS variation were investigated as a function of generation for both dendrimer series. The radius of gyration was found to increase exponentially with generation, whereas the relationship of RMS variation to generation was not as well defined. Density distributions were calculated for all five generations of the organic and organometallic dendrimers. In addition, the distribution of the monomers from each generation within the dendrimer was analysed. In the later generation dendrimers, the monomers belonging to the earlier generations are extended, while the terminal groups are mobile and found in all regions of the dendrimer. The solvent accessible surface was calculated for the organochromium dendrimers. It was concluded from these results that although the terminal groups are mobile, the majority of these monomers remain on the periphery of the dendrimer, or in solvent accessible areas.
Open Access
Computational rationale for the selective inhibition of the herpes simplex virus type 1 uracil-DNA glycosylase enzyme
(2011) Hendricks, Umraan; Naidoo, Kevin J
In this thesis I will investigate the binding pocket and analyse the nature of binding of the 6-(4-Alkylanilino)-uracil inhibitors in hsvUDG and hUDG to provide a platform for the development of improved inhibitors.
Open Access
Computer simulations of a chromatographic column used in the separation of platinum group metal chlorinated complexes
(2012) Michael, Nengwekhulu Thizwilondi; Naidoo, Kevin J; Venter, Gerhard
The PGMs, which are comprised of Ru, Pt, Rh, Ir, Os and Pd, are highly regarded as technologically important precious metals. They have a wide range of applications and are used predominantly as catalysts. These metals are found collectively in nature and hence have similar chemical properties. This makes their separation from contaminants and each other a cumbersome process that requires the most technologically sophisticated refinery processes in metallurgical extraction. An efficient method in which these metal complexes are separated is based on gel chromatography. This uses a concentrated aqueous acidic medium, predominantly hydrochloric acid, and their separation is achieved through differentiation of their different elution orders. However, the similarity in their chemistry makes their separation via current experimental methods difficult.
Open Access
Computing free energy hypersurfaces for anisotropic intermolecular associations
(2009) Strümpfer, Johan; Naidoo, Kevin J
Adaptive reaction coordinate force biaisng methods have been previously used for calculating the free energy of conformation and chemical reactions amongst others. Here a generalized method is described that is able to produce free energies in multiple dimension, descriptively named the free energies from adaptive reaction coordinate forces (FEARCF) method. To illustrate it a multidemensional intermolecular orientational free energy surface is calculated, and it is demonstrated how to invesrigate complex systems such as protein conformation and liquids.
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Computing free energy hypersurfaces for anisotropic intermolecular associations
(Wiley, 2010) Strumpfer, J; Naidoo, Kevin J
We previously used an adaptive reaction coordinate force biasing method for calculating the free energy of conformation (Naidoo and Brady, J Am Chem Soc 1999, 121, 2244) and chemical reactions (Rajamani et al., J Comput Chem 2003, 24, 1775) amongst others. Here, we describe a generalized version able to produce free energies in multiple dimensions, descriptively named the free energies from adaptive reaction coordinate forces method. To illustrate it, we describe how we calculate a multidimensional intermolecular orientational free energy, which can be used to investigate complex systems such as protein conformation and liquids. This multidimensional intermolecular free energy W(r, θ1, θ2, ϕ) provides a measure of orientationally dependent interactions that are appropriate for applications in systems that inherently have molecular anisotropic features. It is a highly informative free energy volume, which can be used to parameterize key terms such as the Gay-Berne intermolecular potential in coarse grain simulations. To demonstrate the value of the information gained from the W(r, θ1, θ2, ϕ) hypersurfaces we calculated them for TIP3P, TIP4P, and TIP5P dimer water models in vacuum. A comparison with a commonly used one-dimensional distance free energy profile is made to illustrate the significant increase in configurational information. The W(r) plots show little difference between the three models while the W(r, θ1, θ2, ϕ) hypersurfaces reveal the underlying energetic reasons why these potentials reproduce tetrahedrality in the condensed phase so differently from each.
Open Access
Conformational analysis of diglycosyl disulphides containing ßS(1-1)S interglycosidic linkages
(2007) Matthews, Richard P; Naidoo, Kevin J
The conformation around the glycosidic linkage has been shown to be the single most important factor in determining the molecular shape of oligosaccharides. This property is of fundamental importance in influencing biological activity such as binding to enzymes or receptors. Therefore, knowledge of the conformational preference associated with glycosidic linkages is required. In this thesis the conformational preferences of the βS( 1-.1 ')8 glycosidic linkage within asymmetrical dissacharide mimetics have been studied using computational methods. The sulphur-sulphur torsion angle parameters contained in the CHARMM22 force field were refined based on density functional theory (OFT) calculations of dimethyl disulphide, which is a representative fragment containing the sulphur-sulphur torsion angle. The refined parameters were then used in molecular dynamics (MD) simulations of three disaccharide mimetics in vacuum, water and dimethyl sulphoxide (OM80). The resulting conformational analysis reveals that in the case of disaccharides containing unsubstituted glycosyl rings, good agreement with experimental nuclear overhauser effects (NOEs) and spin-spin coupling constants is obtained. However, for disaccharides containing substituted glycosyl rings poorer agreement with experimental data is obtained, which may suggest that further refinement of the force field is required. In addition, a natural bond orbital analysis was conducted on the 1, I' - disulphanediyl diethanol fragment to investigate the origin of the conformational preference for the +g and -g conformers of the sulphur-sulphur torsion angle. This phenomenon is shown to be as a result of a two-electron stabilising [no – σ*c-s] delocalisation from the lone pair of the oxygen atoms to the carbon-sulphur antibonding orbitals.
Open Access
The design and development of GPU accelerated algorithms for ab initio integrals and integral derivatives illustrated on ab initio quantum and hybrid QM/MM dynamics
(2016) Renison, Carina Alicia; Naidoo, Kevin J
Graphical Processing Units (GPUs) are highly parallel, programmable accelerators boasting high peak floating point performance. Over the last couple of years the use of GPUs for general purpose computing have revolutionized quantum chemistry. The computational bottleneck in an ab-initio quantum method is the calculation of a large number of twoelectron integrals. To date, a number of GPU accelerated two-electron integral implementations have been developed significantly improving the performance of a static quantum mechanical (QM) calculation. However, when performing an ab-initio QM gradient calculation, optimization, QM or Hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) dynamics simulation the twoelectron integral derivatives arise as an additional bottleneck. Hybrid QM/MM methods particularly dynamics methods are commonly used to study large chemical/biological systems. These methods are a popular choice used for studying reaction mechanisms, conformational and configurational structures important in glycobiology. Usually a semiempirical QM method is used however, these have shown variable accuracy for the study of carbohydrate conformation and prevents an analytical investigation of electronic structure. The use of a higher level of theory, such as an ab initio method, is desirable however this comes at a much greater computational cost. Together with the bottlenecks above this cost results from the polarization of the QM region within an electrostatic embedding scheme, which requires the calculation of a large number of one-electron integral derivatives. Thus for QM/MM calculations the one-electron integral derivatives becomes a third bottleneck together with the two mentioned above. Recently, the above bottlenecks have become popular GPU acceleration targets. This thesis describes an extension of the GPU based Quantum Supercharger Library (QSL) to perform the above calculations/simulations. In contrast to GPU packages developed from the ground up, the QSL is a library of routines aimed at accelerating legacy codes, such as GAMESS-UK, GAMESS-US and NWChem, used in electronic structure calculations. Algorithms are presented for accelerating the one- and two-electron integral derivatives on a GPU. In addition to the derivatives, the one-electron integral calculation was ported to the GPU in order to remove a small additional cost arising for large QM/MM systems. Furthermore, the use of automatic code generation for generating GPU kernels was explored and compared to the original approach. Using the QSL library implemented in GAMESS-UK several benchmark calculations and simulations were performed. These were performed in double precision on a single GPU (Kepler K20) and compared to a single CPU using the 6-31G basis set. A speedup of up to 9.3X is achieved for an ab initio gradient calculation compared to the CPU running an optimized serial version of GAMESS-UK using the Schlegel method. For a single point QM/MM calculation of cellobiose in different sized water spheres (3267-24843 point charges) speedups of between 13X and 34X is achieved. QSL/GAMESS-UK coupled to the CHARMM molecular dynamics package was then used in order to perform accelerated molecular dynamics simulations. Benchmark QM and QM/MM molecular dynamics simulations were performed on cellobiose in vacuo and in a water sphere (45 QM atoms and 24843 point charges respectively). The QSL is able to perform 9.7 ps/day of ab initio QM dynamics and 6.4 ps/day of QM/MM dynamics. Testing of the auto-generated version of the QSL showed better performance for lower angular momentum classes but reduced performance for higher angular momentum classes. The efficiency of the integral and derivative routines within the QSL library was tested on a computationally intense realistic glycobiological condensed phase free energy computation. Ab-initio pucker free energy surfaces/volumes of !-Ribofuranose and !-Glucopyranose in vacuum and in water were computed. These are the first converged Hartree-Fock/MM free energy simulations for these carbohydrates performed in solution. The value of the ab initio Free energy surfaces/volumes was demonstrated through an analysis of solvent polarization effects that are evident through a comparison of the vacuum and solution minimum free energy pathways. In particular the water structure around the pucker conformers, analysis of the primary alcohol distribution as well as analysis of the electronic structure of these conformers reveals that water significantly affects the free energy pathways, primary alcohol distribution and the barriers for inter-conversion between pucker conformers.
Open Access
Developing a triangular tessellation method for the analysis of medium ring pucker conformations
(2013) Khalili, Pegah; Naidoo, Kevin J
The main focus of this thesis is to investigate the relative conformational flexibilities of α-, β- and γ-cyclodextrins in water by analysing their macrocyclic ring puckering motion from Molecular Dynamics (MD) simulations. In particular, the puckering of the CDs is investigated through a coarse grained analysis of full atomistic simulations, where the CD conformational motions are studied on the macrocyclic scale rather than the atomistic scale. The flexibilities of the cyclodextrins (CDs) are then compared to their experimentally-observed aqueous solubility trend in order to try explain the anomalously flow solubility of β-cyclodextrin. β-CD has important applications in industry, such as the pharmaceutical industry, thus exploring the conformational reasons for its low solubility can help to design more effective cyclodextrin-based products in future. The ring puckering of the CDs is measured quantitatively using a reduced system of puckering coordinates based on the method of triangular tessellation. The triangular tessellation definition for monocylic 6-membered rings is first extended to 7- and 8-membered rings, and the corresponding puckering coordinates are derived mathematically. The macrocyclic CD rings are then simplified to monocyclic representations through an appropriate coarse graining of the molecules (specifically, α-, β- and γ-cyclodextrins are simplified to 6-, 7- and 8-sided rings, respectively), and the corresponding triangular tessellation definition is then used to measure their macrocyclic puckering. The rates of decay of the puckering motion are then calculated using time correlation functions, from which the relative flexibilities of the CDs is determined. Probability distributions are also used to investigate the ranges of the CD puckering. In addition, the horizontal contraction and expansion of the macrocyclic rings (termed """"breathing"""" herein) is analysed to supplement the puckering analysis. Puckering coordinates based on the triangular tessellation of 6-membered rings have been used previously to characterise all 38 canonical states of cyclohexane. In this thesis, a systematic procedure is developed to generate the triangular tessellation puckering coordinates of all the canonical states of 6-, 7- and 8-membered rings, and the coordinates for all canonical states of cycloheptane and cyclooctane are subsequently generated. These puckering coordinates can be useful not only in the conformational analysis of cyclohexane, cycloheptane and cyclooctane, but also to quantitatively characterise the conformations of 6-, 7- and 8-membered rings in general, both from experimental and computational studies.
Open Access
Developing analytical tools for saccharides in condensed phases
(1999) Kuttel, Michelle Mary; Naidoo, Kevin J
Carbohydrates are conformationally very complex molecules. It is this complexity that lies at the basis of the important roles that these molecules play in many biochemical and biomaterial systems. Moreover, the unusual response of these macromolecules to their environment allow them to play these often critical roles. This is particularly true for solvated carbohydrates. A knowledge of the molecular structure of carbohydrates is essential for an understanding of their function and the molecular basis of their macroscopic properties. The details of solution structure have proven difficult to probe experimentally, but computer simulations are a means for examining solvent structure directly. In this thesis we develop various computational methods for analysing saccharides in solution and in the solid state. These methods are applied to molecular dynamics simulations of maltose, hexa-amylose and a series of cyclodextrins in solution, in order to investigate the effects of water on these polysaccharides. Maltose is investigated because of its potential as a model for larger polysaccharides comprising α(1 → 4)-linked glucose monomers. Solvation was found to effect the conformations of the saccharides studied considerably. In particular, the range of motion around the glycosidic linkage is increased. Comparison of the dynamics around the glycosidic linkages for the various simulation show that oligosaccharides linked via α(1 → 4) glycosidic linkages have similar behaviour around this linkage. The saccharides studied were found to impose considerable anisotropic structure on the surrounding water which may give insights into their solution properties. In addition to the studies in solution, a recently developed method for analysing the close contacts in crystal structures is applied to crystal structures of cyclodextrin inclusion compounds. It shown to be a useful tool for investigating hydrogen-bonding patterns in the cyclodextrins.
Open Access
Developing methods to construct ring pucker free energy hypersurfaces applied to the analysis of glycosidase enzyme catalytic mechanisms
(2010) Barnett, Christopher Bevan; Naidoo, Kevin J
Carbohydrates consist of one or more sub-units usually various 5- and 6-membered cycles (furanoses and pyranoses) which can twist, bend or flip into a variety of conformers that differ in strain - this is ring puckering. These puckers notably the strained puckering conformers are observed during enzymatically assisted bond formation or cleavage of the glycosidic bonds of carbohydrate substrates. In this thesis, the free energy of ring puckering is calculated by implementing the Hill-Reilly reduced coordinate pucker description into the sampling enhancing Free Energies from Adaptive Reaction Coordinate Forces (FEARCF) method. FEARCF non-Boltzmann simulations of prototypical sugars Î²-Dribose and Î²-D-glucose converged to yield free energy pucker surfaces and volumes when using several semi-empirical QM methods - AM1, PM3, PM3CARB-1 and SCC-DFTB. From this, the accessible puckering conformations and minimum free energy paths of puckering were reasoned An analysis of the furanose and pyranose free energy pucker surfaces and volumes compared with both Density Functional Theory RB3LYP/6-311++G** optimised structures and a Hartree-Fock free energy surface revealed that SCC-DFTB provides the best semi-empirical description of 5- and 6- membered carbohydrate ring deformation. This illustrates that necessary high energy ring conformations observed in enzymatic binding sites requires the enzyme to induce and preserve high energy conformations required for successful hydrolyses and synthesis of the glycosidic bond. To further test this hypothesis, a 5- and 6-membered cycle were studied within enzymatic environments. The polysaccharide cellulose contains Î² 1-4 linked glucose subunit and is degraded by cellulase, a glycosidase. Specifically, the retaining cellobiohydrolase I (CBHI) of Trichoderma Reesei which cleaves cellobiose units from crystalline cellulose.The free energy volumes of puckering for the glucose sub-unit (in the catalytic position of an 8 unit cellulosic fragment - cellooctaose) were calculated and explored in vacuum, water and in the active site of CBHI. It was observed that the binding pocket of enzymes limits the ring pucker and that the active site amino acids preferentially stabilise certain puckering conformations. For CBHI, the first part of the glycosidase reaction is the glycosylation step. This was driven to completion during SCC-DFTB QM/MD FEARCF calculations where GLU212, ASP214 and GLU217 and part of the substrate were treated quantum mechanically. The general hybrid orbital method was used to connect the QM and MM regions. The free energy barriers of glycosylation were computed and the puckering statistics during the conversion of cellooctaose to products were correlated with this. Guanosine, a 5-membered ribose derivative is phosphorylated by Purine Nucleoside Phosphorylase (PNP) in order to salvage the guanine base. The effect of the PNP protein environment on ring pucker was studied by using FEARCF SCC-DFTB QM/MD non Boltzmann free energy calculations to quantify the pucker change induced in guanosine when changing environment from vacuum, to water and to the protein. In vacuo, the E4 and E1 pucker conformers were observed as minima. Upon solvation, the puckering phase space became less restricted with the 3T4 and 2T3 pucker conformers as minima. In the PNP active site pucker became restricted with only the 4E conformer observed.
Open Access
The development of hybrid quantum classical computational methods for carbohydrate and hypervalent phosphoric systems
(2014) Govender, Krishna Kuben; Naidoo, Kevin J; Venter, Gerhard
Ab initio, density functional theory, and semi-empirical methods serve as major computational tools for quantum mechanical calculations of medium to large molecular systems. Semi-empirical methods are most effectively used in a hybrid quantum mechanics/molecular mechanics (QM/MM) dynamics framework. However, semi-empirical methods have been designed to provide accurate results for organic molecules, but often fail to treat hypervalent species accurately due to their use of an sp basis. Recently, significant breakthroughs have been made with the incorporation of d-orbitals into the semi-empirical framework, thereby allowing for accurate modeling of both hypervalent and transition metal systems. Here I consider two methods that adopt this new methodology, namely AM1/d-PhoT and AM1*. Our major focus is the simulation of chemical biological and more specifically chemical glycobiological problems of biochemical interest. When I tested the ability of both AM1/d-PhoT and AM1* to reproduce key metrics in chemical glycobiology (i.e., sugar ring pucker, phosphate participation in transferase reactions) these methods, in combination with the published parameters, performed very poorly. Using the AM1/d-PhoT and AM1* Hamiltonians I set out to re-parameterize these methods aiming to produce holistic biochemical QM/MM toolsets able to simulate fundamental problems of binding and enzyme reactivity in chemical glycobiology. We called these methods AM1/d-CB1 and AM1*-CB1. In the development of these parameter sets I focused specifically on proton transfer, carbohydrate ring puckering, bond polarization, amino acid interactions, and phosphate interactions (facets important to chemical glycobiology). Both AM1/d-CB1 and AM1*-CB1 make use of a variable property optimization parameter approach for the glycan molecular class and its chemical environment. The accuracy of these methods is evaluated for carbohydrates, amino acids and phosphates present in catalytic domains of glycoenzymes, and the are shown to be more accurate for key performance indices (puckering, etc.) and on average across all simulation derived properties (QM/MM polarization, protein performance, etc.) than all other NDDO semiempirical methods currently being used. A major objective of the newly developed AM1/d-CB1 and AM1*-CB1 is to provide a platform to accurately model reactions central to chemical glycobiology using hybrid QM/MM molecular dynamics (MD) simulations. AM1/d-CB1 is applied to a well-known reaction involving purine nucleoside phosphorylase (PNP) and results lead me to conclude that the method shows promise for modelling glycobiological QM/MM systems.
Open Access
Electronic and solvent effects on monosaccharide conformations
(2007) Barnett, Christopher Bevan; Naidoo, Kevin J
The hydroxymethyl group rotational preferences of the monosaccharides glucose and galactose are different from each other and non-intuitive (from a steric point of view) in their preferences for gauche conformers. These molecules exhibit very different biological and thermodynamic properties in, for example their binding to glycosides or their liquid crystalline phases in glycolipids. The preference for gauche conformations has been attributed to solvent effects, stereo-electronic effects and hydrogen bonding; yet the experimentally obtained hydroxymethyl rotational populations have not yet been fully rationalised. In this dissertation, I have used a range of ab initio, Molecular Dynamics (MD), Quantum Mechanics/Molecular Mechanics (QM/MM) and free energy computational methods to resolve and explain this observation. The hydroxymethyl free energy surface was calculated using the Potential of Mean Force (PMF), umbrella sampling and Weighted Histogram Analysis Methods (WHAM). The PMF calculations were performed in the canonical (NVT) ensemble in the gaseous and aqueous phase where each monosaccharide was modelled with Parameter Model 3 for Carbohydrates (PM3CARB-I). Density Functional Theory (OFT) calculations were also carried out and Atoms in Molecules (AIM) and Natural Bond Orbital (NBO) analyses were applied. Gaseous phase simulation results for both glucose and galactose gave hydroxymethyl rotational preferences of gg>tg>gt and gt>gg>tg respectively. These conformational preferences can be rationalised in terms of an intrinsic stereo-electronic effect (found from NBO calculations) and strong intramolecular hydrogen bonding (found in the tg conformer of glucose and the gg conformer of galactose using AIM) in the gaseous phase. The addition of solvent (water) was found to disrupt the intramolecular hydrogen bonding present in the gaseous phase. Hydroxymethyl rotational preferences in the solution phase were gg>gt>tg for glucose and gt>tg>gg for galactose. The population distributions in solution were also calculated for glucose as gg:gt:tg = 59.21 :34.88:0.83 and for galactose as gg:gt:tg = 3.32:79.60: 1 0.15. These populations agree favourably with experimental NMR populations. The solvent conformational preference is dominated by the intrinsic stereoeIectronic effect and steric interactions. The gauche effect in monosaccharides has been successfully rationalised.
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Experimental and time-dependent density functional theory characterization of the UV−Visible spectra of monomeric and μ‑Oxo dimeric ferriprotoporphyrin IX
(American Chemical Society, 2012) Kuter, David; Venter, Gerhard A; Naidoo, Kevin J; Egan, Timothy J
Speciation of ferriprotoporphyrin IX, Fe(III)PPIX, in aqueous solution is complex. Despite the use of its characteristic spectroscopic features for identification, the theoretical basis of the unique UV−visible absorbance spectrum of μ- [Fe(III)PPIX]2O has not been explored. To investigate this and to establish a structural and spectroscopic model for Fe(III)PPIX species, density functional theory (DFT) calculations were undertaken for H2O−Fe(III)PPIX and μ- [Fe(III)PPIX]2O. The models agreed with related Fe(III)porphyrin crystal structures and reproduced vibrational spectra well. The UV−visible absorbance spectra of H2O−Fe(III)PPIX and μ-[Fe(III)PPIX]2O were calculated using time-dependent DFT and reproduced major features of the experimental spectra of both. Transitions contributing to calculated excitations have been identified. The features of the electronic spectrum calculated for μ-[Fe(III)PPIX]2O were attributed to delocalization of electron density between the two porphyrin rings of the dimer, the weaker ligand field of the axial ligand, and antiferromagnetic coupling of the Fe(III) centers. Room temperature magnetic circular dichroism (MCD) spectra have been recorded and are shown to be useful in distinguishing between these two Fe(III)PPIX species. Bands underlying major spectroscopic features were identified through simultaneous deconvolution of UV−visible and MCD spectra. Computed UV−visible spectra were compared to deconvoluted spectra. Interpretation of the prominent bands of H2O−Fe(III)PPIX largely conforms to previous literature. Owing to the weak paramagnetism of μ-[Fe(III)PPIX]2O at room temperature and the larger number of underlying excitations, interpretation of its experimental UV−visible spectrum was necessarily tentative. Nonetheless, comparison with the calculated spectra of antiferromagnetically coupled and paramagnetic forms of the μ-oxo dimer of Fe(III)porphine suggested that the composition of the Soret band involves a mixture of π→π* and π→dπ charge transfer transitions. The Q-band and charge transfer bands appear to amalgamate into a mixed low energy envelope consisting of excitations with heavily admixed π→π* and charge transfer transitions.
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Experimentally Consistent Ion Association Predicted for Metal Solutions from Free Energy Simulations
(American Chemical Society, 2010) Matthews, R P; Naidoo, Kevin J
The calculation of association constants from computer simulations has historically been complicated because of difficulties in validating metal ion force fields for solution simulations. Here we develop a method that produces a force field for divalent metal ions in metal sulfate solutions (i.e., Mg2+SO42−, Ca2+SO42−, Mn2+SO42−, Fe2+SO42−, Co2+SO42−, Ni2+SO42−, Cu2+SO42−, and Zn2+SO42−). Using free energy of perturbation calculations, we are able to calibrate the potential of mean force W(r) for these metal sulfate solutions. The calibrated free energy profiles then allow us to produce association constants for contact, solvent-shared, and solvent-separated ion pairs that are in excellent agreement with available ultrasonic and dielectric spectroscopic data. This metal solution force field is accurate for the calculation of relative free energies from physical and biophysical computer simulations.
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The extent of conformational rigidity determines hydration in nonaromatic hexacyclic systems
(American Chemical Society, 2011) Boscaino, Annalisa; Naidoo, Kevin J
We conducted an ultrasonic study of the hydration number for hexacyclic systems. We find from these experiments that cyclohexane-based molecules such as cyclohexanol and myo-inositol show a very small increase in hydration number despite the large difference in the number of hydroxyl groups present in each of the molecules. There is however a dramatic increase in hydration number when shifting from molecules with a cyclohexane frame to molecules with a cyclopyranose frame particularly glucose. An analysis of classical and quantum molecular dynamics simulation trajectories reveal that the hydration number is strongly linked to the conformational flexibility within the molecule. Cyclopyranose is a more rigid ring system compared with cyclohexane and so its ring fluctuates in a smaller range and frequency. The effect of the ring rigidity is that the hydroxyls tethered to the cyclopyranose ring undergo less positional diffusion compared with those attached to the cyclohexane ring. This allows for long time intermolecular hydrogen bonds between the hydroxyls bonded to cyclopyranose rings and the surrounding waters, which leads to an increase in the hydration numbers of carbohydrates compared with those of hydroxylated cyclohexanes.
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FEARCF a multidimensional free energy method for investigating conformational landscapes and chemical reaction mechanisms
(Springer Verlag, 2011) Naidoo, Kevin J
The development and implementation of a computational method able to produce free energies in multiple dimensions, descriptively named the free energies from adaptive reaction coordinate forces (FEARCF) method is described in this paper. While the method can be used to calculate free energies of association, conformation and reactivity here it is shown in the context of chemical reaction landscapes. A reaction free energy surface for the Claisen rearrangement of chorismate to prephenate is used as an illustration of the method’s efficient convergence. FEARCF simulations are shown to achieve flat histograms for complex multidimensional free energy volumes. The sampling efficiency by which it produces multidimensional free energies is demonstrated on the complex puckering of a pyranose ring, that is described by a three dimensional W(1, 2, 3) potential of mean force.
Open Access
FEARCF: Graph-based software library for multidimensional free energy simulations
(2022) Bruce-Chwatt, Tomas; Naidoo, Kevin J
This thesis presents the efforts to adapt the Free Energy from Adaptive Reaction Coordinate Forces (FEARCF) method into the form of a software library, enabling it to be interfaced with other molecular dynamics (MD) software packages. There exist many methods to calculate the free energy of molecular systems, an important quantity when studying chemical reactions and molecular structures. One of these, FEARCF, was developed at the Scientific Computing Research Unit (SCRU). Previously, this method was restricted to usage within the CHARMM MD software package. Taking inspiration from graph theory and object-orientated design, a successful software library implementation will be demonstrated by presenting results from a range of theories including: classical, ab initio and QM/MM. Simulations are conducted for a range of systems and reaction coordinates including: water, glucose, and the GlcNAc/OGT enzyme-substrate complex.
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Glucose Orientation and Dynamics in α-, β-, and γ-Cyclodextrins
(American Chemical Society, 2008) Naidoo, Kevin J; Gamieldien, M R; Chen, J Y-J; Widmalm, G; Maliniak, A
We investigate, using molecular dynamics (MD) computer simulations, the conformational behavior of α-, β-, and γ-cyclodextrins (CDs). Our analysis of a 30 ns trajectory of CD solution dynamics reveals the underlying conformational behaviours of the CDs that explain their relative flexibility. The distributions of the torsion angles related to the glycosidic linkages, P(ϕ,ψ) were calculated for the three CDs. Most noticeable is the limited range in ϕ torsion rotations compared with ψ rotations for all the CDs. This difference between the three CDs is amplified in the motion and dynamics of their glucose monomers when we monitor their orientational and librational positions relative to the macrocyclic mean plane. The relaxation times of the monomers to their equilibrium orientations follow the pattern γ-CD > α-CD > β-CD. The root-mean-square deviations of the motion of the monomer centers of mass from the mean macrocyclic planes exhibit the same trend.