Chemistry & Biochemistry Research Works
Permanent URI for this collectionhttp://hdl.handle.net/1903/15
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Item Acyclic Cucurbit[n]uril Bearing Alkyl Sulfate Ionic Groups - Electronic Supporting Data(Beilstein Journal of Organic Chemistry, 2025-01-09) Akakpo, Christian; Zavalij, Peter Y.; Isaacs, LyleThis dataset contains the electronic data files that support the publication.Item Quantifying modeling uncertainties in seismic analysis of dams: Insights from an international benchmark study(Wiley, 2023-12-19) Hariri-Ardebili, Mohammad AminAdvances in nonlinear dynamic analysis of dams have not completely resolved concerns over modeling confidence and analysis accuracy. Verification and validation offer accuracy assessment, but uncertainties persist during performance evaluation due to both epistemic (modeling) and aleatory (parametric) sources. Epistemic uncertainties arise from simplifications and modeling techniques. This paper addresses epistemic uncertainties in a gravity dam seismic analysis using data from the International Comnission on Large Dams (ICOLD) benchmark study. While the benchmark formulation included the finite element model of the dam, mechanical material properties, and dynamic loads, participants retained the flexibility to opt for best-practice modeling assumptions, simplifications, and other specifics. Notable response variability emerged, particularly in crack profiles and damage predictions. This study examines sources of variability, quantifying modeling uncertainty for the benchmark problem. More specifically, the modeling variability is quantified using the logarithmic standard deviation, also known as dispersion. This metric enables its incorporation into other seismic risk assessment and fragility studies. Under relatively low-intensity motion (peak ground acceleration [PGA] of 0.18 g in this case), modeling dispersion of 0.45, 0.30, 0.32, and 0.30 were calculated for the maximum dynamic crest displacement, maximum hydrodynamic pressure at the heel, heel and crest maximum acceleration, respectively. Additionally, the dispersion of the failure PGA was determined to be 0.7. Findings underscore the need for systematic seismic response modeling in dam engineering to enhance prediction accuracy. A better understanding of the sources and magnitudes of modeling uncertainties can help improve the reliability of dam seismic analysis and contribute to the development of more effective risk assessment and mitigation strategies.Item Comments regarding “Seismic damage analysis due to near-fault multipulse ground motion” by Guan Chen, Jiashu Yang, Ruohan Wang, Kaiqi Li, Yong Liu, Michael Beer; Earthquake Engineering & Structural Dynamics, 2023(Wiley, 2023-11-27) Hariri-Ardebili, Mohammad AminThis discussion is based on the paper by Chen et al. in 2023 (hereafter referred to as “the original paper/authors”). In their study, the original authors conducted a series of analyses using nonpulse, single-pulse, and multipulse ground motion records, evaluating their impact on a frame structure, a slope, and a gravity dam. Their key finding suggests that multipulse ground motion leads to more severe structural damage compared to nonpulse and single-pulse ground motions. However, it is important to note that the seismic damage analysis of the gravity dam in this paper does not adhere to state-of-the-practice recommendations. Consequently, drawing a definitive conclusion regarding the influence and importance of multipulse ground motion records on the seismic response of concrete dams requires further justification. This necessitates the incorporation of high-fidelity numerical models and probabilistic performance evaluation. We will discuss the significance of modeling assumptions, specifically addressing the dam–rock dynamic interaction in crack propagation and failure in dams.Item Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation(Springer Nature, 2023-11-08) Lemma, Betsegaw; Zhang, Di; Vamisetti, Ganga B.; Wentz, Bryan G.; Suga, Hiroaki; Brik, Ashraf; Lubkowski, Jacek; Fushman, DavidPost-translational modification of proteins with polyubiquitin chains is a critical cellular signaling mechanism in eukaryotes with implications in various cellular states and processes. Unregulated ubiquitin-mediated protein degradation can be detrimental to cellular homeostasis, causing numerous diseases including cancers. Recently, macrocyclic peptides were developed that selectively target long Lysine-48-linked polyubiquitin chains (tetra-ubiquitin) to inhibit ubiquitin-proteasome system, leading to attenuation of tumor growth in vivo. However, structural determinants of the chain length and linkage selectivity by these cyclic peptides remained unclear. Here, we uncover the mechanism underlying cyclic peptide's affinity and binding selectivity by combining X-ray crystallography, solution NMR, and biochemical studies. We found that the peptide engages three consecutive ubiquitins that form a ring around the peptide and determined requirements for preferential selection of a specific trimer moiety in longer polyubiquitin chains. The structural insights gained from this work will guide the development of next-generation cyclic peptides with enhanced anti-cancer activity.Item Structural modulation and spin glassiness upon oxidation in oxygen storage material LnFeMnO4+x for Ln = Y, Lu, and Yb(AIP, 2023-06-12) Li, Tianyu; Liou, Sz-Chian; Hong, Stephanie J.; Zhang, Qiang; Mandujano, H. Cein; Rodriguez, Efrain E.The mixed valence multiferroic LnFe2+Fe3+O4 (where Ln = Y, Lu, and Yb) can reversibly uptake oxygen into its lattice, which is evidenced by a crystallographic phase transition along with the appearance of structural modulations. In this study, we show that the Mn-substituted version of this multiferroic can also be readily oxidized to LnFe3+Mn3+O4.5 revealing similar oxygen storage behavior. Through neutron, electron, and synchrotron x-ray diffraction studies, we observe a structural modulation that we attribute to a displacement wave in the fully oxidized compound. This wave exhibits commensurability with a wavevector q = (−2/7, 1/7, 0). Bond valence summation analysis of plausible interstitial oxygen positions suggests that oxygen insertion likely occurs at the middle of the Fe/Mn–O bipyramid layers. The structural modulation of LnFeMnO4.5 is two-dimensional, propagates along the ab-plane, and is highly symmetric as 12 identical modulation vectors are observed in the diffraction patterns. The nature of the lanthanide, Ln3+, does not seem to influence such modulations since we observe identical satellite reflections for all three samples of Ln = Y, Lu, and Yb. Both LnFeMnO4 and LnFeMnO4.5 display spin glassy behavior with 2D short-range magnetic ordering being observed in LnFeMnO4. Analysis of the neutron diffraction data reveals a correlation length of ∼10 nm. Upon oxidation to LnFeMnO4.5, the short-range magnetic order is significantly suppressed.Item A Pro-Drug Approach for Selective Modulation of AI-2-Mediated Bacterial Cell-to-Cell Communication(MDPI, 2012-03-21) Guo, Min; Gamby, Sonja; Nakayama, Shizuka; Smith, Jacqueline; Sintim, Herman O.The universal quorum sensing autoinducer, AI-2, is utilized by several bacteria. Analogs of AI-2 have the potential to modulate bacterial behavior. Selectively quenching the communication of a few bacteria, in the presence of several others in an ecosystem, using analogs of AI-2 is non-trivial due to the ubiquity of AI-2 processing receptors in many bacteria that co-exist. Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited. The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates. Such differences could be utilized to selectively target QS in specific bacteria amongst a consortium of other species that also use AI-2 signaling.Item Endo-S-c-di-GMP Analogues-Polymorphism and Binding Studies with Class I Riboswitch(MDPI, 2012-11-09) Zhou, Jie; Sayre, David A.; Wang, Jingxin; Pahadi, Nirmal; Sintim, Herman O.C-di-GMP, a cyclic guanine dinucleotide, has been shown to regulate biofilm formation as well as virulence gene expression in a variety of bacteria. Analogues of c-di-GMP have the potential to be used as chemical probes to study c-di-GMP signaling and could even become drug leads for the development of anti-biofilm compounds. Herein we report the synthesis and biophysical studies of a series of c-di-GMP analogues, which have both phosphate and sugar moieties simultaneously modified (called endo-S-c-di-GMP analogues). We used computational methods to predict the relative orientation of the guanine nucleobases in c-di-GMP and analogues. DOSY NMR of the endo-S-c-di-GMP series showed that the polymorphism of c-di-GMP can be tuned with conservative modifications to the phosphate and sugar moieties (conformational steering). Binding studies with Vc2 RNA (a class I c-di-GMP riboswitch) revealed that conservative modifications to the phosphate and 2'-positions of c-di-GMP dramatically affected binding to class I riboswitch.Item Small Molecule Inhibitors of AI-2 Signaling in Bacteria: State-of-the-Art and Future Perspectives for Anti-Quorum Sensing Agents(MDPI, 2013-08-29) Guo, Min; Gamby, Sonja; Zheng, Yue; Sintim, Herman O.Bacteria respond to different small molecules that are produced by other neighboring bacteria. These molecules, called autoinducers, are classified as intraspecies (i.e., molecules produced and perceived by the same bacterial species) or interspecies (molecules that are produced and sensed between different bacterial species). AI-2 has been proposed as an interspecies autoinducer and has been shown to regulate different bacterial physiology as well as affect virulence factor production and biofilm formation in some bacteria, including bacteria of clinical relevance. Several groups have embarked on the development of small molecules that could be used to perturb AI-2 signaling in bacteria, with the ultimate goal that these molecules could be used to inhibit bacterial virulence and biofilm formation. Additionally, these molecules have the potential to be used in synthetic biology applications whereby these small molecules are used as inputs to switch on and off AI-2 receptors. In this review, we highlight the state-of-the-art in the development of small molecules that perturb AI-2 signaling in bacteria and offer our perspective on the future development and applications of these classes of molecules.Item 3D DNA Crystals and Nanotechnology(MDPI, 2016-08-18) Paukstelis, Paul J.; Seeman, Nadrian C.DNA’s molecular recognition properties have made it one of the most widely used biomacromolecular construction materials. The programmed assembly of DNA oligonucleotides has been used to create complex 2D and 3D self-assembled architectures and to guide the assembly of other molecules. The origins of DNA nanotechnology are rooted in the goal of assembling DNA molecules into designed periodic arrays, i.e., crystals. Here, we highlight several DNA crystal structures, the progress made in designing DNA crystals, and look at the current prospects and future directions of DNA crystals in nanotechnology.Item Implementation of Glycan Remodeling to Plant-Made Therapeutic Antibodies(MDPI, 2018-01-31) Bennett, Lindsay D.; Yang, Qiang; Berquist, Brian R.; Giddens, John P.; Ren, Zhongjie; Kommineni, Vally; Murray, Ryan P.; White, Earl L.; Holtz, Barry R.; Wang, Lai-Xi; Marcel, SylvainN-glycosylation profoundly affects the biological stability and function of therapeutic proteins, which explains the recent interest in glycoengineering technologies as methods to develop biobetter therapeutics. In current manufacturing processes, N-glycosylation is host-specific and remains difficult to control in a production environment that changes with scale and production batches leading to glycosylation heterogeneity and inconsistency. On the other hand, in vitro chemoenzymatic glycan remodeling has been successful in producing homogeneous pre-defined protein glycoforms, but needs to be combined with a cost-effective and scalable production method. An efficient chemoenzymatic glycan remodeling technology using a plant expression system that combines in vivo deglycosylation with an in vitro chemoenzymatic glycosylation is described. Using the monoclonal antibody rituximab as a model therapeutic protein, a uniform Gal2GlcNAc2Man3GlcNAc2 (A2G2) glycoform without α-1,6-fucose, plant-specific α-1,3-fucose or β-1,2-xylose residues was produced. When compared with the innovator product Rituxan®, the plant-made remodeled afucosylated antibody showed similar binding affinity to the CD20 antigen but significantly enhanced cell cytotoxicity in vitro. Using a scalable plant expression system and reducing the in vitro deglycosylation burden creates the potential to eliminate glycan heterogeneity and provide affordable customization of therapeutics’ glycosylation for maximal and targeted biological activity. This feature can reduce cost and provide an affordable platform to manufacture biobetter antibodies.