Department of Chemistry and Chemical Biology

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7 Things You Should Know About Virtual Labs
(2020-08-14) Badillo, Joseph; Londino-Smolar, Gina; Savvides, Philippos; Chemistry and Chemical Biology, School of Science
Virtual labs are interactive, digital simulations of activities that typically take place in physical laboratory settings.
A systematic study of the absorbance of the nitro functional group in the vacuum UV region
(Elsevier, 2021-11-15) Cruse, Courtney A.; Goodpaster, John V.; Chemistry and Chemical Biology, School of Science
The nitro functional group (NO) features strongly in compounds such as explosives, pharmaceuticals, and fragrances. However, its gas phase absorbance characteristics in the vacuum UV region (120-200 nm) have not been systematically studied. Gas chromatography/vacuum UV spectroscopy (GC/VUV) was utilized to study the gas phase VUV spectra of various nitrated compounds (e.g., nitrate esters (-R-O-NO), nitramines (R-N-NO), nitroaromatics (Ar-NO), and nitroalkanes (R-NO)). The nitro absorption maximum appeared over a wide range (170-270 nm) and its wavelength and intensity were highly dependent upon the structure of the rest of the molecule. For example, the nitroalkanes exhibited a trend in that the ratio of the relative absorption intensity between these two absorption features between the alkyl group (<150 nm) and the nitro group (200 nm) increases as the molecular weight increases. It was observed that the addition of multiple nitro functional groups on benzene or toluene resulted in an increase in intensity and blue shift from approximately 240 nm-210 nm. Nitrate esters exhibited an absorption between 170 nm and 210 nm and absorbance increased with increasing nitrogen content. The relative diversity of the spectra obtained was analyzed by Principal Component Analysis (PCA) and Linear Discriminant Analysis (LDA). These calculations revealed that the spectra of all the compounds analyzed could be reliably differentiated without any misclassifications.
Accelerated computation of free energy profile at ab initio quantum mechanical/molecular mechanical accuracy via a semi-empirical reference potential. II. Recalibrating semi-empirical parameters with force matching
(The Royal Society of Chemistry, 2019-08-15) Pan, Xiaoliang; Li, Pengfei; Ho, Junming; Pu, Jingzhi; Mei, Ye; Shao, Yihan; Chemistry and Chemical Biology, School of Science
An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire AI-QM/MM corrected reaction free energy profile. For three model reactions (identity SN2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6–31G* level of theory all within 1 kcal/mol with a 20 to 45 fold reduction in the computer time.
Achieving biosensing at attomolar concentrations of cardiac troponin T in human biofluids by developing a label-free nanoplasmonic analytical assay
(RSC, 2017) Liyanage, Thaksila; Sangha, Andeep; Sardar, Rajesh; Chemistry and Chemical Biology, School of Science
Acute myocardial infarction (heart attack) is the fifth leading cause of death in the United States (Dariush et al., Circulation, 2015, 131, e29–e322). This highlights the need for early, rapid, and sensitive detection of its occurrence and severity through assaying cardiac biomarkers in human fluids. Herein we report chip-based fabrication of the first label-free, nanoplasmonic biosensor to assay cardiac troponin T (cTnT) in human biofluids (plasma, serum, and urine) with high specificity. The sensing mechanism is based on the adsorption model that measures the localized surface plasmon resonance (LSPR) wavelength shift of anti-cTnT functionalized gold triangular nanoprisms (Au TNPs) induced by a change of their local dielectric environment upon binding of cTnT. We demonstrate that controlled manipulation of the sensing volume and decay length of Au TNPs together with an appropriate surface functionalization and immobilization of anti-cTnT onto TNPs allows us to achieve a limit of detection (LOD) of our cTnT assay at attomolar concentration (∼15 aM) in human plasma. This LOD is at least 50-fold more sensitive than that of other label-free techniques. Furthermore, we demonstrate excellent sensitivity of our sensors in human serum and urine. Importantly, our chip-based fabrication strategy is extremely reproducible. We believe our powerful analytical tool for detection of cTnT directly in human biofluids using this highly reproducible, label-free LSPR sensor will have great potential for early diagnosis of heart attack and thus increase patients’ survival rate.
Amide Synthesis through the In Situ Generation of Chloro- and Imido-Phosphonium Salts
(ACS, 2020-06) Irving, Charles D.; Floreancig, Jack T.; Laulhé, Sébastien; Chemistry and Chemical Biology, School of Science
We describe a methodology for the amidation of carboxylic acids by generating phosphonium salts in situ from N-chlorophthalimide and triphenylphosphine. Aliphatic, benzylic, and aromatic carboxylic acids can be transformed into their amide counter parts using primary and secondary amines. This functional group interconversion is achieved at room temperature in good to excellent yields. Mechanistic work shows the in situ formation of chloro- and imido-phosphonium salts that react as activating agents for carboxylic acids and generate an acyloxy-phosphonium species.
An Overview of α-Aminoalkyl Radical Mediated Halogen-Atom Transfer
(Wiley, 2023-11-08) Sachidanandan, Krishnakumar; Niu, Ben; Laulhé, Sébastien; Chemistry and Chemical Biology, School of Science
The merging of photocatalysis with halogen-atom transfer (XAT) processes has proven to be a versatile tool for the generation of carbon-centered radicals in organic synthesis. XAT processes are unique in that they generate radicals without requiring the use of strong reductants necessary for the traditional single electron transfer (SET) activation of halides. Pathways to achieve XAT in synthetic applications can be categorized into three major sections: i) heteroatom-based activators, ii) metal-based activators, and iii) carbon-based activators among which α-aminoalkyl radicals have taken the center stage. Access to these α-aminoalkyl radicals as XAT reagents has gained significant attention in the past few years due to the robustness of the reactions, the simplicity of the reagents required, and the broadness of their applications. Generation of these α-aminoalkyl radicals is simply achieved through the single electron oxidation of tertiary amines, which after deprotonation at the α-position generates the α-aminoalkyl radicals. Due to the wide scope of tertiary amines available and the tunable nucleophilicity of α-aminoalkyl radical formed, this strategy has become an attractive alternative to heteroatom/metal-based radicals for XAT. In this minireview, we focus our attention on recent (2020–2023) developments and uses of this robust technology to mediate XAT processes.
Analysis of Biofluids by Paper Spray Mass Spectrometry: Advances and Challenges
(2016-03) Manicke, Nicholas E.; Bills, Brandon J.; Zhang, Chengsen; Department of Chemistry & Chemical Biology, School of Science
Abstract Paper spray MS is part of a cohort of ambient ionization or direct analysis methods that seek to analyze complex samples without prior sample preparation. Extraction and electrospray ionization occur directly from the paper substrate upon which a dried matrix spot is stored. Paper spray MS is capable of detecting drugs directly from dried blood, plasma and urine spots at the low ng/ml to pg/ml levels without sample preparation. No front end separation is performed, so MS/MS or high-resolution MS is required. Here, we discuss paper spray methodology, give a comprehensive literature review of the use of paper spray MS for bioanalysis, discuss technological advancements and variations on this technique and discuss some of its limitations.
Application of Multiple Length Crosslinkers to the Characterization of Gaseous Protein Structure
(American Chemical Society, 2022-09-13) Kit, Melanie Cheung See; Webb, Ian K.; Chemistry and Chemical Biology, School of Science
The speed, sensitivity, and tolerance of heterogeneity of native mass spectrometry, as well as the kinetic trapping of solution-like states during electrospray, makes mass spectrometry an attractive method to study protein structure. Increasing resolution of ion mobility measurements and mass resolving power and range are leading to the increase of the information content of intact protein measurements, and an expanded role of mass spectrometry in structural biology. Herein, a suite of different length noncovalent (sulfonate to positively charged side chain) crosslinkers was introduced via gas-phase ion/ion chemistry and used to determine distance restraints of kinetically trapped gas-phase structures of native-like cytochrome c ions. Electron capture dissociation allowed for the identification of crosslinked sites. Different length linkers resulted in distinct pairs of side chains being linked, supporting the ability of gas-phase crosslinking to be structurally specific. The gas-phase lengths of the crosslinkers were determined by conformational searches and density functional theory, allowing for the interpretation of the crosslinks as distance restraints. These distance restraints were used to model gas-phase structures with molecular dynamics simulations, revealing a mixture of structures with similar overall shape/size but distinct features, thereby illustrating the kinetic trapping of multiple native-like solution structures in the gas phase.
Assessing the accuracy of the isotropic periodic sum method through Madelung energy computation
(2014-04) Ojeda-May, Pedro; Pu, Jingzhi
We tested the isotropic periodic sum (IPS) method for computing Madelung energies of ionic crystals. The performance of the method, both in its nonpolar (IPSn) and polar (IPSp) forms, was compared with that of the zero-charge and Wolf potentials [D. Wolf, P. Keblinski, S. R. Phillpot, and J. Eggebrecht, J. Chem. Phys.110, 8254 (1999)]. The results show that the IPSn and IPSp methods converge the Madelung energy to its reference value with an average deviation of ∼10−4 and ∼10−7 energy units, respectively, for a cutoff range of 18–24a (a/2 being the nearest-neighbor ion separation). However, minor oscillations were detected for the IPS methods when deviations of the computed Madelung energies were plotted on a logarithmic scale as a function of the cutoff distance. To remove such oscillations, we introduced a modified IPSn potential in which both the local-region and long-range electrostatic terms are damped, in analogy to the Wolf potential. With the damped-IPSn potential, a smoother convergence was achieved. In addition, we observed a better agreement between the damped-IPSn and IPSp methods, which suggests that damping the IPSn potential is in effect similar to adding a screening potential in IPSp.
Assigning the EPR Fine Structure Parameters of the Mn(II) Centers in Bacillus subtilis Oxalate Decarboxylase by Site-Directed Mutagenesis and DFT/MM Calculations
(American Chemical Society, 2014-02-12) Campomanes, Pablo; Kellett, Whitney F.; Easthon, Lindsey M.; Ozarowski, Andrew; Allen, Karen N.; Angerhofer, Alexander; Rothlisberger, Ursula; Richards, Nigel G. J.; Department of Chemistry & Chemical Biology, School of Science
Oxalate decarboxylase (OxDC) catalyzes the Mn-dependent conversion of the oxalate monoanion into CO2 and formate. EPR-based strategies for investigating the catalytic mechanism of decarboxylation are complicated by the difficulty of assigning the signals associated with the two Mn(II) centers located in the N- and C-terminal cupin domains of the enzyme. We now report a mutational strategy that has established the assignment of EPR fine structure parameters to each of these Mn(II) centers at pH 8.5. These experimental findings are also used to assess the performance of a multistep strategy for calculating the zero-field splitting parameters of protein-bound Mn(II) ions. Despite the known sensitivity of calculated D and E values to the computational approach, we demonstrate that good estimates of these parameters can be obtained using cluster models taken from carefully optimized DFT/MM structures. Overall, our results provide new insights into the strengths and limitations of theoretical methods for understanding electronic properties of protein-bound Mn(II) ions, thereby setting the stage for future EPR studies on the electronic properties of the Mn(II) centers in OxDC and site-specific variants.

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