Scholarly Works, Chemistry

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Ecological Prevalence and Non-Enzymatic Formation of Imidazolium Alkaloids on Moon Snail Egg Collars
Piedl, Karla; Agee, Caitlyn O.; Tarulli, Anthony G.; Campbell, Rose; Banks, Paige; Buchbinder, Nicklas W.; Williamson, R. Thomas; Mevers, Emily (MDPI, 2026-01-01)
Microorganisms wage constant chemical battles against one another as they compete for space and scarce nutrients, particularly within animal-associated habitats. Here, binary assays were used to investigate chemical interactions among Flavobacteriaceae within Neverita delessertiana egg collars, a moon snail common to the Gulf Coast. Analysis of 140 distinct pairings revealed eight that exhibited growth-inhibitory activity. Chemical evaluation of the crude extract from Cellulophaga omnivescoria EM610, which inhibited the growth of three other Flavobacteriaceae, resulted in the isolation of bacillimidazoles A (1) and E (2), two previously characterized metabolites, isolated from a marine Bacillus species. Further work demonstrated that these compounds are readily formed spontaneously by condensation of 2,3-butanedione with phenethylamine and/or tryptamine. Tandem mass spectrometry analysis of the chemical extracts of individual moon snail egg collars revealed the presence of bacillimidazole A in 62% of the egg collars.
Trifluoromethylation of alkyl electrophiles with ¹¹C- or ¹⁸F-labeled fluoroform for PET applications
Wang, Chao; DeMent, Paul; Jana, Susovan; Hong, Jinsoo; Pike, Victor W.; Liu, Wei (American Association for the Advancement of Science, 2025-12-18)
Continued development of positron emission tomography (PET) tracers is essential for advancing molecular imaging in biomedical research and clinical diagnostics. A long-standing limitation in radiochemistry for PET imaging has been the lack of general methods for radiolabeling trifluoromethyl (CF3) groups at C(sp3) sites, despite their growing prevalence in bioactive molecules and radiopharmaceuticals. Here, we present a general approach for late-stage installation of either a [18F]CF3 or [11C]CF3 group at a C(sp3) site. This method leverages unusual copper-mediated radiotrifluoromethylation of alkyl halides and alkyl carboxylic acids by halogen atom transfer and photoredox catalysis, respectively. More than 50 complex molecules and pharmaceutical agents were efficiently labeled with fluorine-18 (18F) or carbon-11 (11C). Two long-sought-after radioligands, [18F]SL25.1188 and [18F]PS13, were synthesized, providing longer-lived 18F analogs of their 11C counterparts with great promise for human PET imaging.
Biogenic Amine-Containing 1,4-Naphthoquinones Mediate Extracellular Electron Transfer in Lactiplantibacillus plantarum
Blackburn, Benjamin T.; Barton, Joseph; Hoernig, Micah; Brown, Anne M.; Mevers, Emily (American Chemical Society, 2025-09-19)
Lactiplantibacillus plantarum, a lactic acid gut bacterium, uses exogenous quinones to facilitate extracellular electron transfer (EET) via type II NADH dehydrogenase (Ndh2). To probe Ndh2 specificity, we designed and evaluated a library of biogenic amine-substituted 1,4-naphthoquinones in an Ndh2-dependent EET assay. Analysis of mediator Ndh2 binding interactions revealed that activity correlates with key binding interactions. Specifically, mediators containing aromatic substitutions elicit favorable Ndh2 interactions, promoting EET.
The Nobilamides: Potent Biofilm Inhibitors Produced by the Microbiota of Moon Snail Egg Masses
Kyei, Lois; Campbell, Rose; Menegatti, Carla; Mevers, Emily (American Chemical Society, 2025-06-20)
Bacterial biofilm infections have become increasingly challenging to treat as bacteria living in a biofilm state are more resistant to antibiotics and protected from the host immune response. Eradicating biofilm infections generally requires treatment with high doses of antibiotics for prolonged periods; however, the rise in antibiotic resistance further challenges these treatments. Unfortunately, there are no approved drugs that inhibit or disrupt biofilm formation. Here, we leveraged our library of bacteria associated with moon snail egg masses found in Puerto Rico, using mass spectrometry-based metabolomics, to discover biofilm inhibitors. Analysis of a chemical fraction library revealed a set of peptides in fractions exhibiting potent inhibition of Staphylococcus aureus biofilms. Bioassay-guided isolation led to the isolation of lipopeptides, the nobilamides, which were previously shown to possess antibacterial activity and TRPV1 antagonist properties but were never evaluated in a biofilm inhibition assay. A thorough evaluation of the biofilm inhibition activity of A-3302-B and A-3302-A revealed they potently inhibit biofilm formation with IC50 of 161 ± 85 and 598 ± 66 nM, respectively. Interestingly, nobilamide A and B, linear analogs, are 500-fold less active than their cyclic analogs.
Accurate and interpretable representation of correlated electronic structure via Tensor Product Selected CI
Braunscheidel, Nicole M.; Bachhar, Arnab; Mayhall, Nicholas J. (Royal Society Chemistry, 2024-11-06)
The task of computing wavefunctions that are accurate, yet simple enough mathematical objects to use for reasoning, has long been a challenge in quantum chemistry. The difficulty in drawing physical conclusions from a wavefunction is often related to the generally large number of configurations with similar weights. In Tensor Product Selected Configuration Interaction (TPSCI), we use a locally correlated tensor product state basis, which has the effect of concentrating the weight of a state onto a smaller number of physically interpretable degrees of freedom. In this paper, we apply TPSCI to a series of three molecular systems ranging in separability, one of which is the first application of TPSCI to an open-shell bimetallic system. For each of these systems, we obtain accurate solutions to large active spaces, and analyze the resulting wavefunctions through a series of different approaches including (i) direct inspection of the TPS basis coefficients, (ii) construction of Bloch effective Hamiltonians, and (iii) computation of cluster correlation functions.
Rechargeable Manganese Dioxide Hard Carbon Lithium Batteries in an Ether Electrolyte
Xia, Dawei; Rosenberg, Keith; Li, Yilin; Hu, Anyang; Sun, Chengjun; Li, Luxi; Nordlund, Dennis; Sainio, Sami; Huang, Haibo; Lin, Feng (Electrochemical Society, 2024-03-31)
Earth-abundant, cost-effective electrode materials are essential for sustainable rechargeable batteries and global decarbonization. Manganese dioxide (MnO2) and hard carbon both exhibit high structural and chemical tunability, making them excellent electrode candidates for batteries. Herein, we elucidate the impact of electrolytes on the cycling performance of commercial electrolytic manganese dioxide in Li chemistry. We leverage synchrotron X-ray analysis to discern the chemical state and local structural characteristics of Mn during cycling, as well as to quantify the Mn deposition on the counter electrode. By using an ether-based electrolyte instead of conventional carbonate electrolytes, we circumvent the formation of a surface Mn(II)-layer and Mn dissolution from LixMnO2. Consequently, we achieved an impressive similar to 100% capacity retention for MnO2 after 300 cycles at C/3. To create a lithium metal-lean full cell, we introduce hard carbon as the anode which is compatible with ether-based electrolytes. Commercial hard carbon delivers a specific capacity of similar to 230 mAh g-1 at 0.1 A g-1 without plateau, indicating a surface-adsorption mechanism. The resulting manganese dioxide
Why Does Monoamine Oxidase (MAO) Catalyze the Oxidation of Some Tetrahydropyridines?
Price, Nathan J.; Nakamura, Akiko; Castagnoli, Neal; Tanko, James M. (Wiley-V C H Verlag, 2024-05-17)
Results pertaining to the mechanism of the oxidation of the tertiary amine 1-methyl-4-(1-methyl-1-H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3-methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO-B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O2 and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO-catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1 degrees and 2 degrees amines react via one of the currently accepted polar pathways. Steric constraints prevent 3 degrees amines from reacting via a polar pathway. Those select 3 degrees amines that are MAO substrates possess certain structural features (e. g., a C-H bond that is alpha- both to nitrogen and a C=C) that dramatically lower the pKa of the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle. A unifying hypothesis for the mechanism of monoamine oxidize (MAO) catalyzed oxidations is presented. Most 1 degrees and 2 degrees amines are oxidized by MAO via a polar pathway; 3 degrees amines are generally not substrates. However, for tetrahydropyridines (and similarly structured amines), an otherwise unfavorable electron transfer pathway is driven by a facile deprotonation (Le Chatelier's principle) because the resulting neutral radicals are exceptionally stable. image
Synthesis, Characterization, and the Effect of Lewis Bases on the Nuclearity of Iron Alkoxide Complexes
Gwinn, Reilly K.; Williams, Matthew; Latendresse, Trevor P.; Slebodnick, Carla; Troya, Diego; Tarannum, Tasnema; Thornton, Diana A. (American Chemical Society, 2024-04-12)
Inspired by the potential of alkoxides as weak-field ligands and their ability to bridge, we report herein a series of high-spin iron complexes supported by a bis-alkoxide framework (Ph)Dbf. A diiron complex [Fe-2((Ph)Dbf)(2)] (1a) is obtained upon metalation of the ligand, whereas addition of substituted pyridines affords five-coordinate mononuclear iron complexes [(R-Py)(2)Fe((Ph)Dbf)] (2a-4a, R = H, p-Bu-t, p-CF3). The potential for nuclearity control of the metal complexes via auxiliary ligands is highlighted by the formation of asymmetric diiron species [(p-CF3-Py)Fe-2((Ph)Dbf)(2)] (5a) and [(m-CF3-Py)Fe-2((Ph)Dbf)(2)] (6a) with trifluoromethyl substituted pyridines, while electron-rich pyridines only produced monomeric species. Electronic properties analysis via UV-vis, electron paramagnetic resonance, Fe-57 Mossbauer spectroscopy, and time-dependent density functional theory, along with redox capabilities of these complexes are reported to illustrate the effect of nuclearity on reactivity and the potential of these complexes to access higher oxidation states relevant in oxidative chemistry. Species 1a-5a, [(THF)(2)Fe((Ph)Dbf)][PF6] (7), [PyFe((Ph)Dbf)Cl] (2b), and [Py2Fe((Ph)Dbf)][PF6] (2c) were characterized via SCXRD. Indirect evidence for the formation of dimeric Fe(III) species (1b, 5b, and 6b) is discussed.
Hydrothermally Assisted Conversion of Switchgrass into Hard Carbon as Anode Materials for Sodium-Ion Batteries
Li, Yilin; Xia, Dawei; Tao, Lei; Xu, Zhiyuan; Yu, Dajun; Jin, Qing; Lin, Feng; Huang, Haibo (American Chemical Society, 2024-05-23)
Sodium-ion batteries (SIBs) are emerging as a viable alternative to lithium-ion batteries, reducing the reliance on scarce transition metals. Converting agricultural biomass into SIB anodes can remarkably enhance sustainability in both the agriculture and battery industries. However, the complex and costly synthesis and unsatisfactory electrochemical performance of biomass-derived hard carbon have hindered its further development. Herein, we employed a hydrothermally assisted carbonization process that converts switchgrass to battery-grade hard carbon capable of efficient Na-ion storage. The hydrothermal pretreatment effectively removed hemicellulose and impurities (e.g., lipids and ashes), creating thermally stable precursors suitable to produce hard carbon via carbonization. The elimination of hemicellulose and impurities contributes to a reduced surface area and lower oxygen content. With the modifications, the initial Coulombic efficiency (ICE) and cycling stability are improved concurrently. The optimized hard carbon showcased a high reversible specific capacity of 313.4 mAh g(-1) at 100 mA g(-1), a commendable ICE of 84.8%, and excellent cycling stability with a capacity retention of 308.4 mAh g(-1) after 100 cycles. In short, this research introduces a cost-effective method for producing anode materials for SIBs and highlights a sustainable pathway for biomass utilization, underscoring mutual benefits for the energy and agricultural sectors.
Mechanistic Diversity in the Hydrolysis of Sarin by Single Transition-Metal Atoms on MOF-808
Fossum, Carl; Troya, Diego (American Chemical Society, 2024-05-24)
Zr-based metal-organic frameworks (Zr-MOFs) are one of the most promising materials for the decomposition of chemical warfare nerve agents. We present a study of the hydrolysis reaction mechanism of nerve agent sarin catalyzed by Zn(II) and Ti(IV) single atoms on the Zr-MOF MOF-808. We reveal that upon binding of the nerve agent to the catalyst, conformational isomerism leads to a great diversity of hydrolysis reaction mechanisms. Each mechanism follows an addition-elimination sequence but differs markedly in the way the elimination step is accomplished and its energetics. Moreover, while most of the prior work has focused on the HF elimination channel, this work shows that the addition-elimination steps can also lead to isopropanol formation through barriers comparable to those of the HF channel. Additional insight is achieved by high-level electronic structure calculations, including coupled-cluster theory, which allow us to benchmark more efficient DFT techniques commonly used in mechanistic studies of catalytic processes involving transition-metal atoms. Overall, this work reveals new reaction pathways for nerve-agent hydrolysis with lower-lying transition-state energies than previously reported, highlighting the importance of conformational sampling in mechanistic studies of catalytic processes.
Solvent-Mediated, Reversible Ternary Graphite Intercalation Compounds for Extreme-Condition Li-Ion Batteries
Tao, Lei; Xia, Dawei; Sittisomwong, Poom; Zhang, Hanrui; Lai, Jianwei; Hwang, Sooyeon; Li, Tianyi; Ma, Bingyuan; Hu, Anyang; Min, Jungki; Hou, Dong; Shah, Sameep Rajubhai; Zhao, Kejie; Yang, Guang; Zhou, Hua; Li, Luxi; Bai, Peng; Shi, Feifei; Lin, Feng (American Chemical Society, 2024-06-07)
Traditional Li-ion intercalation chemistry into graphite anodes exclusively utilizes the cointercalation-free or cointercalation mechanism. The latter mechanism is based on ternary graphite intercalation compounds (t-GICs), where glyme solvents were explored and proved to deliver unsatisfactory cyclability in LIBs. Herein, we report a novel intercalation mechanism, that is, in situ synthesis of t-GIC in the tetrahydrofuran (THF) electrolyte via a spontaneous, controllable reaction between binary-GIC (b-GIC) and free THF molecules during initial graphite lithiation. The spontaneous transformation from b-GIC to t-GIC, which is different from conventional cointercalation chemistry, is characterized and quantified via operando synchrotron X-ray and electrochemical analyses. The resulting t-GIC chemistry obviates the necessity for complete Li-ion desolvation, facilitating rapid kinetics and synchronous charge/discharge of graphite particles, even under high current densities. Consequently, the graphite anode demonstrates unprecedented fast charging (1 min), dendrite-free low-temperature performance, and ultralong lifetimes exceeding 10 000 cycles. Full cells coupled with a layered cathode display remarkable cycling stability upon a 15 min charging and excellent rate capability even at -40 degrees C. Furthermore, our chemical strategies are shown to extend beyond Li-ion batteries to encompass Na-ion and K-ion batteries, underscoring their broad applicability. Our work contributes to the advancement of graphite intercalation chemistry and presents a low-cost, adaptable approach for achieving fast-charging and low-temperature batteries.
Physically Motivated Improvements of Variational Quantum Eigensolvers
Vaquero-Sabater, Nonia; Carreras, Abel; Orus, Roman; Mayhall, Nicholas J.; Casanova, David (American Chemical Society, 2024-06-10)
The adaptive derivative-assembled pseudo-Trotter variational quantum eigensolver (ADAPT-VQE) has emerged as a pivotal promising approach for electronic structure challenges in quantum chemistry with noisy quantum devices. Nevertheless, to surmount existing technological constraints, this study endeavors to enhance ADAPT-VQE's efficacy. Leveraging insights from the electronic structure theory, we concentrate on optimizing state preparation without added computational burden and guiding ansatz expansion to yield more concise wave functions with expedited convergence toward exact solutions. These advancements culminate in shallower circuits and, as demonstrated, reduced measurement requirements. This research delineates these enhancements and assesses their performance across mono, di, and tridimensional arrangements of H-4 models, as well as in the water molecule. Ultimately, this work attests to the viability of physically motivated strategies in fortifying ADAPT-VQE's efficiency, marking a significant stride in quantum chemistry simulations.
Polysaccharide-based H₂S donors: Thiol-ene functionalization of amylopectin with H₂S-releasing N-thiocarboxyanhydrides
Chinn, Abigail F.; Williams, Noah R.; Miller, Kevin M.; Matson, John B. (Wiley, 2024-09-15)
Polymeric donors of gasotransmitters, gaseous signaling molecules such as hydrogen sulfide, nitric oxide, and carbon monoxide, hold potential for localized and extended delivery of these reactive gases. Examples of gasotransmitter donors based on polysaccharides are limited despite the availability and generally low toxicity of this broad class of polymers. In this work, we sought to create a polysaccharide H2S donor by covalently attaching N-thiocarboxyanhydrides (NTAs) to amylopectin, the major component of starch. To accomplish this, we added an allyl group to an NTA, which can spontaneously hydrolyze to release carbonyl sulfide and ultimately H2S via the ubiquitous enzyme carbonic anhydrase, and then coupled it to thiol-functionalized amylopectin of three different molecular weights (MWs) through thiol-ene "click" photochemistry. We also varied the degree of substitution (DS) of the NTA along the amylopectin backbone. H2S release studies on the six samples, termed amyl-NTAs, with variable MWs (three) and DS values (two), revealed that lower MW and higher DS led to faster release. Finally, dynamic light scattering experiments suggested that aggregation increased with MW, which may also have affected H2S release rates. Collectively, these studies present a new synthetic method to produce polysaccharide H2S donors for applications in the biomedical field.
Regioselective Annulation of 6-Carboxy-Substituted Pyrones as a Two-Carbon Unit in Formal [4+2] Cycloaddition Reactions
Kohanov, Zachary A.; Shuvo, Suzzudul Islam; Lowell, Andrew N. (American Chemical Society, 2024-06-13)
Heterocycles serve as a critical motif in chemistry, but despite being present in more than 85% of pharmaceuticals, there are limited methods for their construction. Here, we describe the incorporation of intact pyrone (2H-pyran-2-one) into larger ring systems via annulation. In a formal [4 + 2] cycloaddition, the pyrone regioselectively accepts a benzylic anion as a nucleophile in a conjugate addition fashion, with the subsequent pyrone-derived enolate attaching to a pendant ester on the initial nucleophile. Subsequent base-driven enolate formation and elimination establish aromaticity of the newly formed ring. After optimization of this process using an NMR-based assessment to overcome solubility and separation challenges, the reaction was successfully applied to a library of 6-ester and -amide-substituted pyrones and using a phenyl ester and other substituted sulfoxides. This technology enables the incorporation of intact pyrone rings into more complex systems, such as for the total synthesis of the natural product thermorubin.
Discovery of Potent, Orally Bioavailable Sphingosine-1-Phosphate Transporter (Spns2) Inhibitors
Foster, Daniel J.; Dunnavant, Kyle; Shrader, Christopher W.; LoPresti, Marion; Seay, Sarah; Kharel, Yugesh; Brown, Anne M.; Huang, Tao; Lynch, Kevin R.; Santos, Webster L. (American Chemical Society, 2024-07-02)
Targeting the S1P pathway has resulted in the development of S1P1 receptor modulators for the treatment of multiple sclerosis and ulcerative colitis. We hypothesize that targeting an upstream node of the S1P pathway may provide an improved adverse event profile. In this report, we performed a structure-activity relationship study focusing on the benzoxazole scaffold in SLB1122168, which lead to the discovery of 11i (SLF80821178) as a potent inhibitor of S1P release from HeLa cells (IC50: 51 +/- 3 nM). Administration of SLF80821178 to mice induced similar to 50% reduction in circulating lymphocyte counts, recapitulating the lymphopenia characteristic of Spns2 null animals. Molecular modeling studies suggest that SLF80821178 binds Spns2 in its occluded inward-facing state and forms hydrogen bonds with Asn112 and Ser211 and pi stacking with Phe234. Taken together, SLF80821178 can serve as a scaffold for future inhibitor development and represents a chemical tool to study the therapeutic implication of inhibiting Spns2.
Chemo-, Regio-, and Stereoselective cis-Hydroboration of 1,3-Enynes: Copper-Catalyzed Access to (Z,Z)- and (Z,E)-2-Boryl-1,3-dienes
Buchbinder, Nicklas W.; Nguyen, Long H.; Beck, Owen N.; Bage, Andrew D.; Slebodnick, Carla; Santos, Webster L. (American Chemical Society, 2024-07-17)
A copper-catalyzed alkyne-selective hydroboration of 1,3-enynes is disclosed, providing access to the previously elusive 2-boryl-1,3-dienes. Using CuOAc, Xantphos, and HBpin, Bpin was installed on the internal carbon of a series of symmetric and nonsymmetric 1,3-enynes, affording products with excellent Z:E selectivity. The utility of the 2-boryl-1,3-diene products was demonstrated by transformation to useful functional groups.
A Green, Fire-Retarding Ether Solvent for Sustainable High-Voltage Li-Ion Batteries at Standard Salt Concentration
Xia, Dawei; Tao, Lei; Hou, Dong; Hu, Anyang; Sainio, Sami; Nordlund, Dennis; Sun, Chengjun; Xiao, Xianghui; Li, Luxi; Huang, Haibo; Lin, Feng (Wiley-V C H Verlag, 2024-10-01)
Lithium-ion batteries (LIBs) are increasingly encouraged to enhance their environmental friendliness and safety while maintaining optimal energy density and cost-effectiveness. Although various electrolytes using greener and safer glyme solvents have been reported, the low charge voltage (usually lower than 4.0 V vs Li/Li+) restricts the energy density of LIBs. Herein, tetraglyme, a lesstoxic, non-volatile, and non-flammable ether solvent, is exploited to build safer and greener LIBs. It is demonstrated that ether electrolytes, at a standard salt concentration (1 m), can be reversibly cycled to 4.5 V vs Li/Li+. Anchored with Boron-rich cathode-electrolyte interphase (CEI) and mitigated current collector corrosion, the LiNi0.8Mn0.1Co0.1O2 (NMC811) cathode delivers competitive cyclability versus commercial carbonate electrolytes when charged to 4.5 V. Synchrotron spectroscopic and imaging analyses show that the tetraglyme electrolyte can sufficiently suppress the overcharge behavior associated with the high-voltage electrolyte decomposition, which is advantageous over previously reported glyme electrolytes. The new electrolyte also enables minimal transition metal dissolution and deposition. NMC811||hard carbon full cell delivers excellent cycling stability at C/3 with a high average Coulombic efficiency of 99.77%. This work reports an oxidation-resilient tetraglyme electrolyte with record-high 4.5 V stability and enlightens further applications of glyme solvents for sustainable LIBs by designing Boron-rich interphases.
Kinetics of Calcite Nucleation onto Sulfated Chitosan Derivatives and Implications for Water-Polysaccharide Interactions during Crystallization of Sparingly Soluble Salts
Knight, Brenna M.; Mondal, Ronnie; Han, Nizhou; Pietra, Nicholas F.; Hall, Brady A.; Edgar, Kevin J.; Welborn, Valerie Vaissier; Madsen, Louis A.; De Yoreo, James J.; Dove, Patricia M. (American Chemical Society, 2024-07-11)
Anionic macromolecules are found at sites of CaCO3 biomineralization in diverse organisms, but their roles in crystallization are not well-understood. We prepared a series of sulfated chitosan derivatives with varied positions and degrees of sulfation, DS(SO3-), and measured calcite nucleation rate onto these materials. Fitting the classical nucleation theory model to the kinetic data reveals the interfacial free energy of the calcite-polysaccharide-solution system, gamma(net), is lowest for nonsulfated controls and increases with DS(SO3-). The kinetic prefactor also increases with DS(SO3-). Simulations of Ca2+-H2O-chitosan systems show greater water structuring around sulfate groups compared to uncharged substituents, independent of sulfate location. Ca2+-SO3- interactions are solvent-separated by distances that are inversely correlated with DS(SO3-) of the polysaccharide. The simulations also predict SO3- and NH3+ groups affect the solvation waters and HCO3- ions associated with Ca2+. Integrating the experimental and computational evidence suggests sulfate groups influence nucleation by increasing the difficulty of displacing near-surface water, thereby increasing gamma(net). By correlating gamma(net) and net charge per monosaccharide for diverse polysaccharides, we suggest the solvent-separated interactions of functional groups with Ca2+ influence thermodynamic and kinetic components to crystallization by similar solvent-dominated processes. The findings reiterate the importance of establishing water structure and properties at macromolecule-solution interfaces.
Revisiting Artifacts of Kohn-Sham Density Functionals for Biosimulation
Slattery, Samuel A.; Yon, Jaden C.; Valeev, Edward F. (American Chemical Society, 2024-07-31)
We revisit the problem of unphysical charge density delocalization/fractionalization induced by the self-interaction error of common approximate Kohn-Sham (KS) density functional theory functionals on simulation of small to medium-sized proteins in a vacuum. Aside from producing unphysical electron densities and total energies, the vanishing of the HOMO-LUMO gap associated with the unphysical charge delocalization leads to an unphysical low-energy spectrum and catastrophic failure of most popular solvers for the KS self-consistent field (SCF) problem. We apply a robust quasi-Newton SCF solver [] to obtain solutions for some of these difficult cases. The anatomy of the charge delocalization is revealed by the natural deformation orbitals obtained from the density matrix difference between the Hartree-Fock and KS solutions; the charge delocalization not only can occur between charged fragments (such as in zwitterionic polypeptides) but also involves neutral fragments. The vanishing-gap phenomenon and troublesome SCF convergence are both attributed to the unphysical KS Fock operator eigenspectra of molecular fragments (e.g., amino acids or their side chains). Analysis of amino acid pairs suggests that the unphysical charge delocalization can be partially ameliorated by the use of some range-separated hybrid functionals but not by semilocal or standard hybrid functionals. Last, we demonstrate that solutions without the unphysical charge delocalization can be located even for semilocal KS functionals highly prone to such defects, but such solutions have non-Aufbau character and are unstable with respect to mixing of the non-overlapping "frontier" orbitals. Caution should be exercised when unexpectedly small (or vanishing) HOMO-LUMO gaps and atypical SCF convergence patterns (e.g., oscillatory) are observed in KS DFT simulations in any context (bio or otherwise).
Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents
Cheng, Yao; Jones, John Patrick; Yu, Tsz Tin; Olzomer, Ellen M.; Su, Jacky; Katen, Alice; Black, David StC; Hart-Smith, Gene; Childress, Elizabeth S.; Wilkins, Marc R.; Mateos, Isabel A.; Santos, Webster L.; Hoehn, Kyle L.; Byrne, Frances L.; Kumar, Naresh (Academic Press-Elsevier, 2024-10-01)
Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10 via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC50 of 2.60 mu M, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

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