Browsing by Author "Wilkinson, Karl A"

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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.
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    Identification of natural product stereochemistry via calculation of ECD spectra
    (2018) Lolli, Riccardo; Venter, Gerhard A; Wilkinson, Karl A; Terenziani, Francesca
    Most commercially available antibiotics are obtained from natural products, secondary metabolites of bacteria or other living organisms. Due to the importance of this class of compounds in medicinal chemistry and growing drug resistance, efforts to discover, characterize and isolate new or improved antibiotics are continually increasing. The assignment of the absolute configuration (AC) adopted by these compounds is a crucial aspect of the characterization step and knowledge of the stereochemistry is an important factor in deciphering the interaction of these compounds with the organism and thus, the mechanism of action. In order to assign the AC, several techniques, such as X-ray diffraction and NMR experiments as well as the standard electronic spectroscopy experiments (UV-Vis, ECD, etc.) or less widespread vibrational and rotational spectroscopy experiments (VCD, ROA, etc.) can be used, often in combination. However, sophisticated synthetic strategies or difficult isolation of the natural compound often leads to a small amount of product available, making some of the previous techniques unpractical; in addition to the potential structural complexity of the molecule, this can make the experimental assignment of the AC problematic. For this reason, a computational approach, aimed at calculating observable properties of the products, generating spectra and assigning the AC through comparison between the calculated and the experimental spectra, has proven useful in many cases. Formicamycin is a natural product, isolated from a new member of Streptomyces bacteria, which has shown great activity against pathogenic drug-resistant bacteria and fungi, without developing antimicrobial resistance. This dissertation shows that the chiral axis of Formicamycin can be assigned as R, through the calculation of electronic circular dichroism (ECD) spectra and comparison to the experimentally determined spectrum in methanol. ECD spectroscopy is very sensitive to the chiral environment of chromophores and can be used to distinguish between different isomers. The computational procedure has been broadly defined in previous studies and involves three general steps: 1) generation of an ensemble of structures, 2) optimization of the structures and calculation of the rotational strengths of each and 3) generation of the Boltzmannweighted spectrum. Here, two different force fields (OPLS3 and MMFFs) were used for generating the ensemble of conformers, followed by PBE0 DFT calculations to determine the optimal geometry and finally, TDDFT calculations to compute the rotational strengths of each conformer. Furthermore, the spectra were calculated in four different solvents, using the implicit SMD method, in order to inform future studies about “variable solvent circular dichroism”. Different conformations of a molecule can be controlled by the choice of solvent and it is hypothesised that a change in solvent will result in a “fingerprint” shift in the ECD spectra that could permit assignment of the stereochemistry. The entire process was automated using a module written in Python.
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    Molecular details from computational reaction dynamics for the cellobiohydrolase I glycosylation reaction
    (American Chemical Society, 2011) Barnett, Christopher B; Wilkinson, Karl A; Naidoo, Kevin J
    Glycosylation of cellobiose hydrolase I (CBHI), is a key step in the processing and degradation of cellulose. Here the pathways and barriers of the reaction are explored using the free energy from adaptive reaction coordinate forces (FEARCF) reaction dynamics method coupled with SCC-DFTB/MM. In many respects CBHI follows the expected general GH7 family mechanism that involves the Glu-X-Asp-X-X-Glu motif. However, critical electronic and conformational details, previously not known, were discovered through our computations. The central feature that ensures the success of the glycosylation reaction are the Glu212 nucleophile’s hydrogen bond to the hydroxyl on C2, of the glucose in the −1 position of the cellulosic strand. This Glu212 function restricts the C2 hydroxyl in such a way as to favor the formation of the 4E ring pucker of the −1 position glucose. A frontier molecular orbital analysis of the structures along the reaction surface proves the existence of an oxocarbenium ion, which has both transition state and intermediate character. The transition state structure is able to descend down the glycosylation pathway through the critical combination of Asp214 (HOMO), ring oxygen (LUMO), and Glu212 (HOMO), anomeric carbon (LUMO) interactions. Using the fully converged FEARCF SCC-DFTB/MM reaction surface, we find a barrier of 17.48 kcal/mol separating bound cellulose chain from the glycosylated CBHI. Taking recrossing into account gives kcat = 0.415 s–1 for cellobiohydrolase glycosylation.
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    Molecular details from computational reaction dynamics for the cellobiohydrolase I glycosylation reaction
    (American Chemical Society, 2011) Barnett, Christopher B; Wilkinson, Karl A; Naidoo, Kevin J
    Glycosylation of cellobiose hydrolase I (CBHI), is a key step in the processing and degradation of cellulose. Here the pathways and barriers of the reaction are explored using the free energy from adaptive reaction coordinate forces (FEARCF) reaction dynamics method coupled with SCC-DFTB/MM. In many respects CBHI follows the expected general GH7 family mechanism that involves the Glu-X-Asp-X-X-Glu motif. However, critical electronic and conformational details, previously not known, were discovered through our computations. The central feature that ensures the success of the glycosylation reaction are the Glu212 nucleophile’s hydrogen bond to the hydroxyl on C2, of the glucose in the −1 position of the cellulosic strand. This Glu212 function restricts the C2 hydroxyl in such a way as to favor the formation of the 4E ring pucker of the −1 position glucose. A frontier molecular orbital analysis of the structures along the reaction surface proves the existence of an oxocarbenium ion, which has both transition state and intermediate character. The transition state structure is able to descend down the glycosylation pathway through the critical combination of Asp214 (HOMO), ring oxygen (LUMO), and Glu212 (HOMO), anomeric carbon (LUMO) interactions. Using the fully converged FEARCF SCC-DFTB/MM reaction surface, we find a barrier of 17.48 kcal/mol separating bound cellulose chain from the glycosylated CBHI. Taking recrossing into account gives kcat = 0.415 s–1 for cellobiohydrolase glycosylation.