Browsing by Author "Rauk, Arvi"

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    Bridging the Gap Between the Theoretical and Empirical Reorganization Energy
    (2016-01-29) Johannes, Jonathan; Sanders, Barry; Salahub, Dennis; Noskov, Sergei; Wieser, Michael; Rauk, Arvi
    Biological electron transfer (ET) reactions are fundamental to the production of energy in all living cells. Efficient, site-selective ET is crucial for effective metabolic processes to sustain life. An accurate description of the ET process through a protein complex is lacking. In particular, with the methylamine dehydrogenase (MADH) and amicyanin protein complex there is a discrepancy between the theoretical and the empirical reorganization energy. Attempts at better understanding the reorganization energy of reaction involve adapting Marcus theory, the standard for simple ET reactions, by describing the reorganization energy with a two-parameter model. In this thesis I apply the two-parameter model to the MADH-amicyanin system. It does not reconcile the discrepancy between the theoretical and empirical reorganization energy. The results of this work provide insight, consistent with other systems onto which the two-parameter has been applied, into why Marcus theory breaks down.
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    Calculation of multiplet and bond energies by the HFS- method
    (1978) Ziegler, Tom; Rauk, Arvi
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    Copper binding to the beta amyloid peptide of alzheimer's disease
    (2007) Raffa, Duilio Federico; Rauk, Arvi
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    Designing Novel Peptidic Inhibitors of Beta Amyloid Oligomerization
    (2010) Roy, Samir Sudhir; Rauk, Arvi
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    Excited-State Studies with the Constricted Variational Density Functional Theory (CV-DF) Method
    (2016) Seidu, Issaka; Rauk, Arvi; Ziegler, Tom (deceased); Salahub, Dennis; MacCallum, Justin; Nooijen, Marcel; Sanders, Barry
    Theoretical calculations have played a vital role in understanding electronic properties of chemically and electronically relevant systems. Some of the roles played by theoretical approaches include the assignment and interpretation of spectra of chemical species such as the transition metal (TM) complexes. However, before these theoretical methods can be used as predictive tools in the chemical analysis of compounds for which experimental results are unavailable, the performance and scope of applicability of these methods must be well understood and improvements made wherever necessary. In this work, the Constricted Variational Density Functional Theory (CV-DFT) method is used in detailed analyses of excited-state properties of TM and other chemical species. Studies are carried out with the CV-DFT method in areas where the adiabatic Time-Dependent Density Functional Theory (ATD-DFT) method have been found insufficient, such as charge transfer (CT) and Rydberg excitations, as well as areas where ATD-DFT performed well. This was done to ensure that, the CV-DFT method not only show good performance for excitations poorly described by ATD-DFT but those that are sufficiently described as well. For a better understanding of the strengths and weaknesses of the CV-DFT methods, our calculated results are compared to experimental and/or high level ab initio results whenever available. Finally, an extension is made to CV-DFT for double excitation. These double excitations are known to be important for excited-state studies in conjugated systems such as the polyenes. Future work will be carried to examine the performance of this method. We find, in general, that CV-DFT shows accurate performance for excitations that are poorly described by the ATD-DFT method, and comparable performance for excitations in which ATD-DFT performs adequately.
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    In Silico Ligand Design to Inhibit Oligomerisation and Cu+ Redox Activity in Alzheimer’s Disease
    (2018-04-20) Opare, Stanley; Rauk, Arvi; Salahub, Dennis; Noskov, Sergei; Wildering, Willem; Storr, Tim
    Alzheimer’s disease (AD) is a progressive disease of the brain. It leads to the loss of memory and thinking abilities. The toxicity has been associated with smaller oligomeric forms of beta amyloid peptide (beta amyloid). The speed of aggregation has been attributed to pH changes attributing fastest aggregation to pH ranging from 5 to 6. Generation of reactive oxidative species (ROS) has also been attributed to the cause of this disease. This process has been attributed to Fenton-like chemistry involving copper. Cu+ has been associated with reduction of O2 to O2•-; reduction of O2•- to H2O2; and further reduction of H2O2 to form HO•. Because of these, Cu+ was targeted in designing ligands that will bind stronger Cu+ than how much beta amyloid will. Beta amyloid complexes Cu+ using His13 and His14. Using quantum mechanical (QM) approach, the binding energy of both oxidation states of copper bound to two histidines and additional water molecules to complete the coordination where necessary (to model the interaction in Ab) were generated and the reduction potential estimated. Armed with this information, ligands were designed that mimic the Cu+ coordination in beta amyloid. The Gibbs free energies of both Cu+ and Cu2+ coordination to these ligands in addition to their reduction potentials were also calculated and compared to that in the model beta amyloid complex. The ligands were ranked accordingly and possible drug (ligand) candidates predicted. One of the ligand candidates (PI) was attached to a pseudopeptide called SGC1 which was designed to inhibit oligomerization. Molecular dynamics and umbrella sampling approaches were used to ascertain their inhibition of beta amyloid self oligomerization. By so doing this new pseudopeptide will serve both purposes of inhibiting oligomerization and generation of reactive oxidative species. Due to computational cost the region of beta amyloid that was used was the so called self recognition site and the region that binds to Cu+. This region covers from His13 to Asp23. This region is referred to as Rec and is used as a model for beta amyloid.
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    In Silico Studies of Peptide-Peptide Interactions: Relevance to Amyloid Beta Peptide Aggregation in Alzheimer’s Disease
    (2016) Petoyan, Anahit; Rauk, Arvi; Tieleman, Peter; Kusalik, Peter; Noskov, Sergei
    Alzheimer's disease is a progressive, chronic fatal disease of the brain where the amyloid beta (Aβ) peptide appears in its oligomeric forms, which are known to be neurotoxic. One way to stop this neurotoxicity is to prevent self-oligomerization of Aβ peptide. In the literature, it was shown that Aβ binds to itself in the region of Aβ (13-23) referred as the self-recognition site (Rec). In our lab, several pseudopeptides (referred as Ligands) were designed to bind with Aβ (13-23). Computational chemistry techniques such as Molecular Dynamics Simulations and Umbrella Sampling have been utilized to characterize the Ligands that are intended to bind selectively to the Rec. It has been observed that the Ligands bind to Rec, Aβ (13-23), and they are competitive with it, suggesting that these Ligands can compete with the full length of Aβ as well. Thus, they could be considered as “drug” candidates to stop Aβ oligomerization.
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    Lewis Acidity and Basicity: An Ab Initio Study of Proton and BF3 Affinities of Oxygen- Containing Organic Compounds
    (American Chemical Society, 1994) Rauk, Arvi; Hunt. Ian R.; Keay, Brian A.
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    On the Involvement of Copper Binding to the N-Terminus of the Amyloid Beta Peptide of Alzheimer's Disease: A Computational Study on Model Systems
    (2011-12-01) Azimi, Samira; Rauk, Arvi
    Density functional and second order Moller-Plesset perturbation theoretical methods, coupled with a polarizable continuum model of water, were applied to determine the structures, binding affinities, and reduction potentials of Cu(II) and Cu(I) bound to models of the Asp1, Ala2, His6, and His13His14 regions of the amyloid beta peptide of Alzheimer's disease. The results indicate that the N-terminal Asp binds to Cu(II) together with His6 and either His13 or His14 to form the lower pH Component I of Aβ. Component II of Aβ is the complex between Cu(II) and His6, His13, and His14, to which an amide O (of Ala2) is also coordinated. Asp1 does not bind to Cu(II) if three His residues are attached nor to any Cu(I) species to which one or more His residues are bound. The most stable Cu(I) species is one in which Cu(I) bridges the Nδ of His13 and His14 in a linear fashion. Cu(I) binds more strongly to Aβ than does Cu(II). The computed reduction potential that closely matches the experimental value for Cu(II)/Aβ corresponds to reduction of Component II (without Ala2) to the Cu(I) complex after endergonic attachment of His6.
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    Quantum Chemical Predictions of the Stable Isotope Distribution of Copper in Blood Serum
    (2017) Tennant, Alexander; Wieser, Michael; Ouyed, Rachid; Rauk, Arvi
    Changes in the stable isotope composition of copper in blood serum as a result of biological processes in the liver were quantified. The model calculated reduced partition function ratios corresponding to interactions involving individual proteins using Density Functional Theory. This quantified the effect that each process had on the redistribution of copper isotopes in the liver. It was not possible to calculate the reduced partition function of CTR1 and an optimization process was used to constrainthe possible isotopic fractionation associated withinteractions involving CTR1. The exchange of copper between ceruloplasmin and ATP7B has the most significant impact on the copper isotopic composition of blood serum. In the absence of values for reduced partition functions and protein concentrations for other processes in the liver, the possible distribution of copper isotopes in the liver was estimated. It was found that there may be large intracellular copper isotope abundance variations in hepatocytes.
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    Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2. Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings
    (American Chemical Society, 1997) Bures, Edward; Nieman, James A.; Yu, Shuyuan; Spinazzé, Patrick G.; Bontront, Jean-Louis J.; Hunt, Ian R.; Rauk, Arvi; Keay, Brian A
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    The Optical activity of Dienes: alpha-phellandrene
    (1979) Peoples, Hugh Allan; Rauk, Arvi
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    Understanding β-Sheets in Alzheimer’s Disease to Confront it
    (2018-07-10) Mehrazma, Banafsheh; Rauk, Arvi; Salahub, Dennis; Tieleman, Dirk Peter; Fraser, Marie E.; DiLabio, Gina A.
    Based on the β-amyloid peptide (Aβ) hypothesis, Alzheimer’s disease develops when generation and clearance of Aβ become imbalanced. As a result, the peptide goes through structural changes, and establishes aggregates with high β-sheet content. In this thesis, the core hydrophobic region of the peptide, Aβ13-23, designated as “R”, is under investigation. The potency of a series of pseudo-peptides (PP) to block the aggregation of R, as a model of full-length Aβ42, are benchmarked by applying molecular dynamics (MD) and umbrella sampling calculations (MD-US). The effective binding free energy, ΔGeff, is used as a criterion to estimate the inhibitory ability of PPs. The all-L-amino acid PP, SGC1 and the all-D-amino acid SGB1 were predicted to have the highest anti-Aβ aggregation effect. The results are supported by experimental studies. The Electrospray ionization mass spectroscopy on R and one of PPs, named as SGA1, yielded a free energy of dissociation similar to MD-US. The PPs with the highest estimated inhibitory efficacy were further investigated against full-length Aβ42. All the PPs influence the overall structure of the monomeric Aβ. Two methods were exploited to examine the free energy of binding: i) a combination of GROMOS96 53a5 force field gas-phase energies and the Poisson-Boltzmann solvent accessible (PBSA) method, and ii) an improved linear interaction energy (LIE-D) technique. The ranking for PP-Aβ complexes for both methods were almost always consistent with MD-US results on PP-R complexes. The best PPs predicted to inhibit Aβ aggregation are the all-L amino acid inverso SGC1 and the all-D amino acids SGB1 and SGD1. Finally, the Aβ42 dimer conformations were investigated by a total of 9.5 μs MD simulations. The results from cluster analysis and energy calculations suggests that besides the Aβ13-23 (R) region, the C-terminal region of Aβ42 peptide plays an important role in β-sheet formation.
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