Chemistry & Chemical Biology Department Theses and Dissertations

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Optically Switchable Molecular Machine-Inspired Nanoplasmonic Sensing Platforms for Early Cancer Detection
(2025-05) Langlais, Sarah R.; Sardar, Rajesh; Naumann, Christoph; Deng, Yongming; Goodpaster, John
Disease diagnostics enable physicians to diagnose cancer and monitor at-risk disease associated pathology sub-populations enabling implementation of lifesaving treatment at the earliest timepoint to improve patient prognosis. However, limitations in biosensing sensitivity and specificity at the point of disease onset and during the early stages of pathogenic progression have hindered identification of biomarkers capable of early clinical diagnostics. Moreover, it has been well documented in literature that the combination of multiple biomarkers from different bimolecular classes, such nucleic acids, proteins, exosomes and exosomal cargo molecules, increases both sensitivity and specificity while mitigating false responses for early cancer diagnostics when marker concentrations and concentration changes occur at extremely low levels. However, to date, scientists have been limited in this endeavor to combining various laboratory techniques in order to pool assay results of a diverse groups of biomarkers from various bimolecular classes. For example, modern bioanalytical techniques such as drop digital or quantitative reverse transcription polymerase chain reaction (ddPCR, qRT-PCR), next generation sequencing (NGS), mass spectrometry (MS) and electrochemistry have been used to assay nucleic acids, while lateral flow assay (LFA), western blot (WB), SERS and enzyme-linked immunosorbent assay (ELISA) are routinely utilized for detection and quantification of proteins. Furthermore, exosomes and exosomal cargo molecules have been assayed using nanopores, microarrays, immunoassays and fluorescence. However, these techniques are also hindered with high occurrences of false positive responses, are extremely labor intensive, require amplification and/or fluorescent labeling, and have extensive sample processing requirements. To overcome these challenges and improve accuracy, diagnostic technology has sought to develop a single platform with multiplex functionality that is also capable of adaptive detection of multiple types of biomarkers simultaneously using a single instrument. Current literature for multiplexed and multiparametric assay capability has been limited to microRNA and Protein detection with nanopores, plasmonics, PCR or mass spectrometry and detection of exosomes and exosomal cargo molecules achieved using microfluidic devices and fluorescence. Unfortunately, there has yet to be a single platform capable for adaptively assaying microRNA, proteins, exosomes and exosomal cargo molecules simultaneously, under identical device constructs in addition to, a device capable of achieving the unprecedented sensitivity and specificity needed for early cancer diagnostics. In this dissertation, a novel localized surface plasmon resonance (LSPR)-based sensing mechanism is introduced and utilized in the development of a photo-switchable molecular machine-inspired diagnostic platform. LSPR is a highly studied nanoscale phenomenon resulting from the oscillations of free electrons on the surface of metallic noble metal nanostructures when irradiated with light. These oscillations can be collected to produce dipole spectral absorption peaks and result in strong electromagnetic near-field enhancements ideal for developing optoelectronic devices. Consequently, this property is highly dependent, and tunable, based on the size, shape and composition of the nanostructure employed. Sensing mechanisms utilizing this phenomenon are conducted by observing a change in absorbance, bulk refractive index, and local refractive index. In this dissertation, a fourth novel mechanism is identified involving the dipole-dipole coupling interactions between the free electrons on the surface of the nanostructure and a zwitterionic spiropyran/merocyanine-based surface ligand. This innovative mechanism is utilized for the fabrication of an optically switchable molecular machine-inspired nanoplasmonic sensor (OSMINS)-based diagnostic platform capable of highly sensitive and specific adaptable assays for multiparametric analysis of patient biofluids. Additionally, the multiplex functionality on the OSMINS platform is ideal for rapid, and both label and amplification-free sample processing. The work presented in this dissertation is presented in five chapters, including: (1) Introduction. (2) Methods. (3) Dipole-dipole coupling mechanism elucidation and utilization in optoelectronic device fabrication to detect microRNA and protein for bladder cancer diagnosis. In this chapter, a new LSPR-based sensing mechanism was identified and explored through the development of a novel single nanostructure-zwitterionic organic molecule coupled plasmonic ruler (PR). A dipole-dipole coupling mechanism is hypothesized and supported through theoretical calculations on dipole polarizability using an inorganic-organic heterodimer model and experimentally by determining work function and interfacial dipole values. A PR is first fabricated utilizing different Au nanostructures (triangular nanoprisms (TNPs), bipyramids (BiPs) and rods (NR)) and then when TNPs and BiPs are found to generate a superior LSPR response, further optimization of the spiropyran (SP) surface concentration via SP-spacer self-assembled monolayer (SAM) ratios is investigated. Given the synergistic relationship between LSPR-based optoelectronic device fabrication and light activated molecular machines, the new dipole-dipole coupling mechanism and PR construct is employed to fabricate an adaptable photo-switching (APS) nanoplasmonic biosensor. The singleplex-based APS biosensor is employed to detect microRNA and protein in human plasma and urine, respectively, for bladder cancer diagnosis. This regenerative and reusable APS biosensor is shown to achieve a femtomolar limit of detection (LOD) assaying 10-healthy control (HC) and 10-metastatic bladder cancer patients attaining p values ranging from 0.0002-0.0001. (4) Fabrication and optimization of an optically-switchable molecular machine-inspired nanoplasmonic sensor (OSMINS)-based diagnostic platform is achieved and utilized in performing microRNA and protein singleplexing assays for early diagnosis of pancreatic cancer (PDAC) from at-risk disease associated pathologies. In this chapter, alkylthiol linker length is optimized for SP bound to TNPs to achieve an ultrasensitive attomolar concentration LOD for detecting circulating microRNA and protein. Two-dimensional conditioned cellular media studies and orthotopically implanted PDAC cell NOD scid gamma (NSG) mouse model study is conducted to assess OSMINS diagnostic potential for early PDAC diagnosis. The OSMINS platform is then deployed to assay oncogenic microRNA and protein in 11-PDAC, 20-chronic pancreatitis (CP), 6-intraductal papillary mucinous neoplasm (IPMN), and 20-HC patients achieving p values of 0.0001 (PDAC vs. HC, IPMN vs. HC), 0.0332 (CP vs. HC) and 0.1234 (PDAC vs. CP, IPMN vs. CP). Biostatistical analysis is used to pool biomarker results, meaning microRNA + protein, to improve CP vs. HC, PDAC vs. CP and IPMN vs. CP comparison p values to 0.0001. Cross-validation of the OSMINS platform is also presented using ddPCR and electrochemiluminescence (ECL) for microRNA and protein assays, respectively, showing excellent correlation. (5) Fabrication of a multiplexed and multiparametric OSMINS-based platform with receptor structure engineered molecular machine-enabled fully customizable assays of circulating microRNA, protein, exosomes and exosomal cargo molecules for early pancreatic cancer detection and prediction of Neoadjuvant chemotherapy (NAC) treatment response. Based on the results, a predictive model is developed for early cancer detection and patient monitoring. In this work, the previously presented OSMINS technology from chapter 4 is expanded and deployed to fabricate a 96 multi-well, high-throughput device for simultaneous assays of multiple biomarkers from various biomolecular classes in a single instrument run, allowing for direct comparison of results for the first time. OSMINS development from a singleplex solid-state biosensor into a multiplexed and multiparametric diagnostic platform is reported and assessed via three-dimensional conditioned cellular media study and a PDAC specific Patient-Derived Xenograft (PDX-21) mouse model study. The multiplexed and multiparametric OSMINS platform is then used to analyze 20-PDAC, 14-low grade IPMN, 6-high grade/invasive IPMN and 20-HC patient plasma samples for direct assay of microRNA, protein and exosomes as well as isolation of exosomes and assay of exosomal lysate for protein and microRNA cargo molecules. This work achieved p values ranging from 0.0001 to 0.1234, which is discussed in detail with regard to type of assay and marker biomolecular classes designation. Validation of multiplexed and multiparametric OSMINS platform is conducted via ddPCR, ELISA, and nanoparticle tracking analysis for microRNAs, proteins and exosomes, respectively. Finally, multiplexed and multiparametric OSMINS-based platform is utilized for 15-PDAC patients before and during NAC treatments to evaluate microRNA and protein biomarkers for their effectiveness in predicting NAC treatment response. Taken together, our multifaceted detection approach utilizing a novel multiplexed and multiparametric OSMINS-based sensing platform represents a paradigm shift in accessing the full diagnostic potential of current and future identified circulating biomarkers and their biomolecular cargo for early cancer diagnosis, monitoring of at-risk associated pathogenic conditions, and as predictive markers for patient treatment response.
Structural Comparison of Denatured and Supercharged Proteins in Gas and Solution Phases
(2025-05) Cain, Rebecca; Basu, Partha; Webb, Ian; Manicke, Nicholas; Naumann, Christoph; Larriba-Andaluz, Carlos
Mass spectrometry has become a popular tool for studying large biomolecules due to its high sensitivity. Mass spectrometry techniques like ion mobility separation and fragmentation methods allow for top-down analysis to determine protein structures. As a gas phase technique, it is crucial to understand how ions fold or unfold in the gas phase without the support of solvents/water, as well as how they behave during the various energy and pressure changes experienced throughout the instrument. It is especially important to understand how protein gas phase ions behave and to monitor any major structural changes occurring since protein structure directly influences protein function. There is a plethora of structural studies that aim to retain native protein structure without additives or the disruption of native salt bridges and inter- and intra- molecular bonds. However, more work is needed on non-native proteins. This work analyzes denatured and supercharged proteins using different mass spectrometry techniques to compare the solution and gas phase structures. First, measuring the amount of unfolding under various denaturing and instrument conditions helps to identify how denatured protein ions behave in the gas phase without the presence of solvent. Next, comparing denatured structures using solution and gas phase crosslinking identifies specific structural changes as proteins unfold, as well as tracks how well protein denaturation retains solution phase structure in the gas phase. Finally, protein supercharging helps to enhance mass spectrometry analysis by shifting charge state distributions towards a lower m/z range. By comparing a supercharged protein’s ATDs and CCS values, we can measure any influence supercharging has on protein structure. Crosslinking supercharged proteins also allows for a comparison of structure and can help confirm how supercharging agents add charge to proteins. Similar structures between solution and gas phases help to substantiate mass spectrometry as a robust tool for proteomic studies. Structural differences between the two phases facilitate the interpretation of gas phase phenomena for mass spectrometry analysis and highlights how solvent influences protein structure.
Campylobacter jejuni Periplasmic Nitrate Reductase NapA as a Medium for Elucidating Molybdenum Cofactor Reactivity
(2025-05) Metzger, Mikayla; Basu, Partha; Blacklock, Brenda; Webb, Ian; Pu, Jingzhi
Periplasmic nitrate reductase NapA is found within many gram-negative bacteria and catalyzes oxygen atom transfer reactions. NapA utilizes nitrate as a terminal electron acceptor in place of oxygen in low-air conditions, such as in the human gastrointestinal tract. Within the scope of this thesis, NapA from Campylobacter jejuni is primarily focused due to its reputation in poultry husbandry and antibiotic resistance. Although nitrate reduction aids in pathogen survival, it is also a geochemically essential process. Many enzymes closely related to NapA are involved in geochemical cycling and contain the same active site ligand structure. The ligand within these enzymes is called molybdenum cofactor, or Moco. The structure of the enzyme is influential on reactivity of the molybdenum cofactor. The rate of catalysis, electron and proton transfer, and substrate preference can be affected by the amino acids surrounding Moco. Elucidating details of Moco reactivity aids in understanding bacteria in relation to human health and geochemical cycles. The primary tools throughout this research were site-directed mutagenesis and steady-state kinetics.
Chemometric Comparison Of GC-MS And GC-VUV For The Trace Analysis Of Methamphetamine
(2024) Lyle, Grant; Goodpaster, John; Sardar, Rajesh; Manicke, Nicholas
Chemometrics, the application of mathematical or statistical algorithms to make inferences on the state of a chemical system from physical measurements of it, is a powerful tool that can be used to re-read what previously was observed as ‘noise’ in analytical measurements. Instruments such as spectrophotometers can take thousands of measurements over a predefined interval, but the spectra are only of great use when reference libraries exist, or if large trends occur that allow for visual matching, such as with a particular functional group. Application of statistical techniques to these data, such as principal component analysis (PCA) and linear discriminant analysis (LDA), can help to spot underlying variances, and differentiate between similar spectra by using linear combinations of these variables for classification. Methamphetamine (MA) is a member of the phenethylamines, a group of compounds that act as central nervous system stimulants, which are highly addictive and often the subject of law enforcement efforts at the local and federal level. Use of derivatization agents in analysis of seized narcotics is common practice, as it increases volatility/thermal stability of analytes, and improves peak shape for chromatographic resolution. In this analysis, we looked to investigate the difference in instrumental response for MA in its native form, as well as derivatized with two common agents, acetic anhydride and trifluoroacetic anhydride. These three forms were analyzed both on a gas chromatograph- mass spectrometer (GC-MS) and a gas chromatograph- vacuum ultraviolet spectrometer (GC-VUV). The raw GC-MS and GC-VUV data were separately normalized, and the dimensionality of the data was reduced through PCA, which uses orthogonal linear transformations of the data to capture most of the variance between datasets while simultaneously reducing the dimensionality for further analysis. Linear discriminant analysis was utilized to look at the principal components from PCA, and a classification model was built for use in discriminating between forms of methamphetamine from compressed datasets.
Development of Polymer Gel-Supported Lipid Bilayer Using Capillary-Assisted Assembly
(2024-12) Chuduang, Kridnut; Naumann, Christoph A.; Long, Eric C.; Sardar, Rajesh; Lin, Chien-Chi
The modern view of the plasma membrane is that of a complex, highly dynamic, compartmentalized system that critically impacts multiple important cellular functions. Supported model membranes of well-defined compositions have emerged as attractive experimental platforms to determine the underlying molecular processes that regulate membrane-associated cellular functions using advanced biophysical detection methods with up to single molecule resolution. However, membrane properties of previously employed supported membrane systems, such as solid-supported lipid bilayer (SLB) and polymer-supported lipid bilayer with a polymer layer thickness of several nm, were found to be perturbed by the nearby solid substrate. To overcome this limitation, the present work describes for the first time the capillary-assisted formation of a lipid bilayer (CA-PGB) on the surface of a fully hydrated, several micrometers thick polyacrylamide gel. CA-PGB formation can be accomplished by physisorption or specific chemical linkages (tethering) between polymer gel and bilayer. Not dissimilar to conditions found in plasma membranes, membrane properties of CA-PGB are found to be solely influenced by the attached polymer layer. The successful formation and lipid fluidity of CA-PGB is confirmed using confocal microscopy and fluorescence correlation spectroscopy (FCS). Lipid bilayer spreading on the hydrogel surface by capillary-assisted assembly is not altered when the polymer gel stiffness or bilayer bending stiffness are varied, illustrating the robustness and versatility of the assembly process. This work also shows that, unlike other supported membrane systems, the capillary-assisted assembly approach causes the formation of a lipid reservoir at the edge of the capillary. This lipid reservoir provides a lipid supply for the CA-PGB, enabling bilayer self-healing and superior bilayer stability relative to SLB. Experimental data are presented that support an assembly process, in which bilayer spreading on the gel surface inside the water capillary between two substrates is caused by monolayer collapse of suddenly accumulated lipids at the air-water interface of the capillary during sandwiching. A key aspect of the monolayer collapse-induced bilayer spreading is its rapid kinetics, which appears to be faster than the polymer gel swelling kinetics. The importance of the fast kinetics of bilayer spreading during capillary-assisted assembly is supported by the observation that attempts to build polymer gel-supported lipid bilayer using traditional lipid assembly methods [i. e., Langmuir-Blodgett (LB)/Langmuir-Schaefer (LS), LB- vesicle fusion, and spontaneous bilayer spreading from a hydrated lipid source], characterized by slower bilayer spreading kinetics, are unable to form a homogeneous fluid lipid bilayer on the polymer gel surface. The experimental results obtained in this work strongly suggest that the CA-PGB not only represents a powerful experimental model membrane platform for the analysis of membrane-associated processes relevant in cellular membranes, but also serves as promising cell surface mimetic to probe the cellular mechanosensitivity of adherend cells.
Expanding the Capabilities of Paper Spray Mass Spectrometry: High-Throughput Drug Screening and On-Paper Electrokinetic Stacking
(2024-12) Rydberg, Magnus Per; Manicke, Nicholas; Deiss, Frédérique T.; Web, Ian K.; Naumann, Christoph T.
Paper spray mass spectrometry (PS-MS) offers advantages in simplicity and rapid analysis but faces challenges that have limited its widespread adoption. These include insufficient sensitivity for certain analytes, susceptibility to matrix effects in complex samples, and inconsistent quantitative performance. Such limitations have restricted the application of PS-MS in fields requiring high sensitivity in analysis of complex biological matrices. This dissertation explores approaches to enhance the capabilities and applications of PS-MS, with a particular focus on overcoming sensitivity limitations. Chapter 2 demonstrates the potential of PS-MS in forensic toxicology through an automated high-throughput urine drug screening method. Chapter 3 investigates the negative impact of laser cutting paper spray substrates on sensitivity and provides practical remedies. The core of this work revolves around the development and application of electrokinetic stacking coupled to PS-MS. Chapter 4 describes the integration of field-amplified sample stacking and faradaic ion concentration polarization into paper-based MS ionization cartridges. Chapter 5 presents mathematical modeling to complement the experimental work, offering a theoretical framework for understanding system behavior. Chapter 6 demonstrates practical applications of the technique, utilizing stacking devices to detect low levels of per- and polyfluoroalkyl substances (PFAS) in tap water and drugs of abuse in urine. These applications demonstrate substantial enhancements in sensitivity over conventional PS-MS, while preserving the technique's advantage of minimal sample preparation. Moreover, this work also identifies a potential path towards incorporating electrokinetic separations in PS-MS, addressing a longstanding limitation of the technique and potentially broadening its applicability in complex sample analysis.
Photoinduced Pyridine N-Oxide Catalyzed Functionalization of Unactivated Olefins and Alkylboronic Acids
(2024-12) Ascenzi Pettenuzzo, Cristina; Deng, Yongming; Minto, Robert; Laulhé, Sébastien; Sardar, Rajesh
Primary alcohols are fundamental substrates in organic synthesis, and widely used in pharmaceutical, agrochemical, and bulk/fine chemical industries. Chapter one describes the current practices in industry and discoveries in academia for primary aliphatic alcohol synthesis. The methods discussed in chapter one include hydroboration-oxidation, the Ziegler process, hydroformylation/hydrogenation, transition metal-catalyzed hydrogenation of epoxides. Catalytic methods are described as well, both in transition metal catalysis and photoredox catalysis. Chapter two introduces a photoinduced pyridine N-oxide-catalyzed method for carbohydroxylation of unactivated olefins. The extensive reaction optimization process is shown, including the screening of different pyridine N-oxides, photocatalysts, and solvents. In this chapter, the applicability of the method is confirmed for a broad scope of unactivated olefins, both mono- and di-substituted. The regioselectivity of the transformation is confirmed by X-ray crystallography. Chapter three offers mechanistic insights regarding the carbohydroxylation of unactivated olefins. The proposed mechanism is corroborated through different experiments. Cyclic voltammetry and Stern-Volmer fluorescence quenching analysis, revealed that the photocatalyst directly oxidized pyridine N- oxide but does not oxidize the olefin substrate. The substitution step that ultimately affords the primary alcohol is confirmed with the use of different oxygen nucleophiles, that generate the corresponding carbo-oxygenated products. The 18O labeling experiments provide solid evidence that the oxygen source is not the pyridine N-oxide, rather it is the added nucleophile. Radical trapping experiments confirm the existence of the carbon radical generated, after pyridine N-oxy radical addition to the olefin. Chapter four delves in the development of a protocol for the generation of alkyl carbon radicals from alkylboronic acids, wherein photoexcited 4-nitropyridine N-oxide biradical features a catalyst to promote the nucleo-homolytic substitution of boronic acids. With a wide range of readily available aliphatic boronic acids, including methyl boronic acid, the developed catalytic system demonstrates broad applicability for alkylation, amination, and cyanation.
Development Of Paper Spray Mass Spectrometry Cartridges With Solid Phase Extraction For Drug Screening Applications
(2024-12) Jakstonyte Ren, Greta ; Manicke, Nicholas; Goodpaster, John; Naumann, Christoph; Deiss, Frédérique
The rise in overdoses, especially due to synthetic drugs like fentanyl has demonstrated a need for a rapid and simple drug detection method. This work describes the development and optimization of a paper spray mass spectrometry (PS-MS) with integrated solid-phase extraction (SPE) cartridges that can detect a wide range of drugs in plasma and whole blood The results can be obtained providing results in under five minutes with minimal sample preparation. The method is highly adaptable, allowing for rapid response to new emerging drugs. The initial focus on synthetic cannabinoids demonstrated sub-0.1 ng/mL detection limits for eight compounds in 100 µL of plasma. This work was expanded to screen thirty-five analytes from drug classes including fentanyl analogs, cathinones, benzodiazepines, and traditional illicit drugs. Validated according to SWGTOX guidelines, all drugs were detected in low ng/mL ranges. A streamlined data analysis method was also developed using a decision tree algorithm and an in-house library of nearly 200 compounds. This enabled retrospective analysis and detection of emerging drugs, such as 4F-MDMB-BINACA and brorphine, from previous samples. In a study of 400 authentic overdose plasma samples, 102 unique drugs were identified, mostly fentanyl-related. To further simplify the process, an "all-in-one" SPE cartridge was developed for whole blood, effectively pre-concentrating over 20 drugs of abuse. This device showed single and sub-ng/mL detection limits in 70 µL of blood. Samples were stable for 14 days, demonstrating the system’s potential for rapid, practical applications in forensic and clinical settings.
Mass Spectrometry Assay Development for Small Molecule Drug Therapies and Drugs of Abuse
(2024-12) Zimmerman-Federle, Hannah MacKenzie; Manicke, Nicholas; Goodpaster, John; Deiss, Frédérique; Deng, Yongming
Mass spectrometry (MS) is a comprehensive and adaptable technique that is useful for addressing a wide range of complex analytical challenges. In this work MS-based assays were developed to address issues relating to the synthetic drug epidemic and failures in point-of-care situations. Chapter one is an overview of the history of mass spectrometry, the fundamental operation of a mass spectrometer, and the advancements made in ionization methods. Chapter two is a review focusing on drug surveillance programs, or lack thereof, and their impact on combating the synthetic drug epidemic in the United States. The work in chapter three describes the development of a novel untargeted semiquantitative paper spray mass spectrometry assay for synthetic drug screening in human plasma. This work implemented a 3D printed solid phase extraction cartridge that allowed for sample preconcentration. This method was tested using remnant patient plasma samples collected from local downtown Indianapolis hospitals. Chapter four introduces a comparison of mass spectrometry acquisition methods to determine the most sensitive and specific techniques. The acquisitions that are compared are parallel reaction monitoring (PRM), sequential windowed acquisition of all theoretical mass (SWATH), and data dependent acquisition (DDA). A small subset of synthetic drugs with known properties were chosen for this comparison and a confirmation study was conducted with real patient samples. Chapter five describes the development of a paper spray mass spectrometry assay for the detection and semi quantitation of � -Lactam antibiotics to improve point-of-care therapeutic drug monitoring in critical care patients in the pediatric population. A liquid chromatography mass spectrometry method was also developed to compare limits of detection between these two methods. Single lot patient plasma samples were tested using both methods and the lower limits of detection and quantitation were compared. Chapter six details a combined approach for the determination of methylpyridine derivative isomers utilizing gas chromatography infrared spectroscopy (GC-IR), gas chromatography mass spectrometry (GC-MS), and density functional theory (DFT) calculations. The projects detailed herein show the extensive range with which mass spectrometry can be used for the detection of a wide range of drugs and synthetic compounds.
The Influence of Structure on the Donor-Acceptor Properties of Metallodithiolene Complexes
(2024-08) Colston, Kyle J.; Basu, Partha; Deng, Yongming; Pu, Jingzhi; Laulhé, Sébastien
The intrinsic charge transfer properties of a given system are dictated by their electronic structure. The movement of electrons from electron rich to electron deficient moieties of a system can spur useful photophysical properties that have been utilized in the development of materials science. Such systems take advantage of redox-active ligands, which can actively participate in electron transfer, and have the versatility to function as either electron donors or acceptors in charge transfer processes. One of the most widely used family of ligands in the development of such materials is dithiolene (Dt), which can exists in two redox extremes; reduced ene-1,2-dithiolate(2-) (Dt2-) and oxidized dithione (Dt0). Dt ligands draw inspiration from the molybdenum cofactor (Moco) found in molybdenum containing enzymes that are present in all phyla of life. The Dt2- and Dt0 ligands play contrasting roles in charge transfer, however, characterization of their electronic structure when both are incorporated into a coordination complex is underexplored. Detailed computational and experimental interrogation of such complexes are presented to highlight the importance of molecular and electronic structures on their charge transfer properties. Such complexes containing a Mo core are also relevant towards the comprehension of the electronic structure of Moco. This investigation focuses on the fundamental understanding of the charger transfer properties of metallodithiolene complexes containing both Dt2- and Dt0 ligands, and progress towards the synthesis of the closest Moco analogs.

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