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Beta-Sheet Mimics: A Step Towards Targeting Protein-Protein Interactions

Type: Undergraduate
Author(s): Brett Thorell Chemistry & Biochemistry Alex Menke Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: First Floor, Table 6, Position 1, 1:45-3:45

Small molecules are reliable and pervasive pharmaceuticals because critical drug characteristics are predictable including solubility and membrane permeability. In addition, small molecules are typically inexpensive to produce and their mechanisms of action subscribe to a common paradigm vis-à-vis blocking an enzyme active site. In contrast, nature employs elaborate machinery to make large molecules, oftentimes rings (or macrocycles). Drug companies avoid these because the rules for predicting behavior are under-explored and the paradigm used for action is different vis-à-vis blocking protein-protein interactions. Moreover, they are costly and laborious to make. To contribute to an understanding of drug design for large molecules, our group is preparing a series of large molecules (macrocycles). The lead adopts a beta-sheet conformation in the solid state, but its behavior in solution is unknown. Here, a second member of the class is described wherein alanine replaces glycine in the macrocycle to provide additional handles to study conformation and the effects that structure has on critical parameters. The 26-atom macrocycle is synthesized in a three-step process. The reaction of a triazine core, and the addition of BOC-hydrazine, alanine, and dimethylamine yields the first intermediate which undergoes elaboration with a 4-carbon acetal group using traditional peptide-coupling strategies (HBTU). Dimerization of the resulting monomer occurs in a 1:1 mixture of dichloromethane and trifluoroacetic acid. Reaction progress is followed by thin-layer chromatography and the identity of the products is confirmed by 1H and 13C NMR spectroscopy. Conformational analysis rests on 2-D 1H NMR spectroscopy. The molecule will also be subjected to analysis for solubility and membrane permeability. In the longer term, these beta-sheet mimics will be used to disrupt protein-protein interactions with an emphasis on the BRCA1-PALB2 interaction implicated in breast cancer.

(Presentation is private)



Type: Undergraduate
Author(s): George Weimer Biology Alexa Frattini Chemistry & Biochemistry
Advisor(s): Jeffrey Coffer Chemistry & Biochemistry
Location: Basement, Table 5, Position 2, 11:30-1:30

Utilizing the supportive structure of hydrogels, the semiconducting character of porous silicon (pSi) membranes, and the biodegradability of both, a unique biosensor for the chemical analysis of health-relevant analytes can ideally be created.
Alginate-based hydrogels are water-infused, biodegradable polymer networks. These are particularly useful because of their environmental abundance, and their ability to interface well with human skin. These characteristics also make them an ideal medium for supporting pSi membranes and simultaneously assimilating them into a wide range of tissues.
Porous silicon (pSi), a highly porous form of the elemental semiconductor, is utilized to measure and conduct electrical signals throughout the hydrogel matrix. In diode form, these membranes exhibit measurable current values as a function of voltage, which can be used to detect bioelectrical stimuli such as the concentration of physiologically relevant ionic species (e.g. Na+, K+, and Ca2+).
Recent experiments center on integrating pSi membranes into various aqueous environments and hydrogels to test how variations in ion concentration affect the flow of electrical current as a function of applied voltage. pSi membranes are fashioned into diodes upon the attachment of 0.25 mm diameter copper wire using silver epoxy and annealing. An electrochemical cell is created by placing two pSi membranes parallel each other in an electrolyte composition. Current is measured as a function of applied voltage (typically from 0-5 V) for systems with differing NaCl concentration.
As expected, the magnitude of maximum current response is proportional to ion concentration present in the electrolyte, with an order of magnitude amplification or more of measured current for a given voltage upon immersion of the electrodes in an alginate hydrogel matrix relative to water alone.
This presentation will focus on initial diode fabrication protocols, as well as establishing limits of detection for simple ions species present in human sweat. More refined strategies are also envisioned, including the development of methods for stabilization of sensor performance along with miniaturization of the sensing platform itself.

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Testing a Computation Workflow for Drug Design: pKa and logP from the SAMPL7 Blind Challenge

Type: Undergraduate
Author(s): Katherine Zabel Chemistry & Biochemistry
Advisor(s): Benjamin Janesko Chemistry & Biochemistry
Location: Third Floor, Table 4, Position 3, 1:45-3:45

Testing a Computational Workflow for Drug Design: pKa and logP from the SAMPL7 Blind Challenge
Katie Zabel
Advisor: Benjamin Janesko
Being able to produce accurate predictions of pKa for various molecules is an ongoing effort in computational chemistry. Drug companies and industries are constantly seeking accurate predictions of pKa and lipophilicity for molecules that are possible drug candidates. Accurate predictions of these values means that time, money, and effort won’t be wasted synthesizing molecules that aren’t going to be effective drugs. The Janesko group has developed a workflow that uses CREST for conformational analysis and (M11plus/def2TZVP/SMD) DFT calculations to identify a molecule’s pKa. The DFT calculations process and refine the relative energies of the stable conformations. The goal of this project is to benchmark the current workflow against the SAMPL7 challenge, which will test the workflow’s outperformance of the best quantum-mechanical methods from 2021. The SAMPL challenge is a competition that asks participants to predict the properties of molecules that have never been synthesized. These molecules will then be created in labs and their properties will be accurately tested. Comparison of the competitor's predicted properties to the true values measured will assess the accuracy of the competitor's predictions. If the prediction of pKa using the current workflow is accurate based off the benchmark against the SAMPL7 challenge, then the workflow could be entered into the next SAMPL Blind challenge.

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Directed evolution of RimJ for N-terminal protein acetylation with broad substrate specificity

Type: Undergraduate
Author(s): Anastasia Bernal Chemistry & Biochemistry Youngha Ryu Chemistry & Biochemistry
Advisor(s): Youngha Ryu Chemistry & Biochemistry
Location: Basement, Table 7, Position 1, 1:45-3:45

N-terminal acetylation is essential for the stability, activity, and targeting of proteins in eukaryotes. However, most eukaryotic proteins are not acetylated when expressed in bacteria. Therefore, it is of practical significance to control N-terminal acetylation of recombinant proteins in bacteria. RimJ is an N-terminal acetyltransferase (NAT) known to acetylate many recombinant proteins with a narrow substrate specificity in E. coli. This project is aimed to increase the applicability of RimJ for the N-terminal acetylation of a broad range of recombinant proteins.
Based on the AlphaFold-predicted structure of E. coli RimJ, we predicted that six amino acids (Y35, E46, R49, Y106, Y170, and L171) may recognize substrate proteins in the active site. We created RimJ variants, in which one or two of these amino acids are changed to alanine, a small neutral amino acid, so that the active site becomes larger to accommodate substrate proteins containing bigger N-terminal amino acid residues. The RimJ variants were created using site directed mutagenesis, confirmed by DNA sequencing, and co-expressed with Z domain mutants that were not acetylated by the wildtype RimJ. The Z domain mutants were isolated by immobilized metal ion affinity chromatography and analyzed by mass spectrometry for their N-terminal acetylation patterns.

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Building a Library of TB Drugs

Type: Undergraduate
Author(s): Grace Bobo Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Basement, Table 9, Position 1, 11:30-1:30

In the past two centuries, tuberculosis (TB) has killed over 2 billion people. TB is an airborne contagious infection that usually attacks the lungs and can spread to the brain and spine. Today TB is treated with 6-12 months of antibiotics and if the medication is ended early the treatment is ineffective. There are also drug resistant forms of TB that are caused by mutations of the bacteria and this process is sped up by the overprescribing of antibiotics which is a growing problem. Dr. Jeffrey Aube created a drug that attacked both non replicating and replicating TB bacteria in the body. This was a major step from previous medicines that could only attack one. We are creating a library of TB drugs that are customizable, efficiently made, and easily purified. These customizable drugs will not only create a large range of effective medicines but also can treat TB that is resistant to antibiotics. Tuberculosis is still one the leading infectious disease killer today, claiming 1.5 million lives annually and we are making drugs that could change that and save millions of lives.

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Impacts of Indole Moiety Location on Pyridinophane Activity

Type: Undergraduate
Author(s): Will Campa Chemistry & Biochemistry Christina Mantsorov Biology Shrikant Nilewar Chemistry & Biochemistry Kristof Pota Chemistry & Biochemistry
Advisor(s): Kayla Green Chemistry & Biochemistry
Location: Second Floor, Table 1, Position 3, 11:30-1:30

Pyridinophane molecules have recently been shown to have both antioxidant and pharmacological properties suitable for therapeutic applications targeting neurodegenerative diseases, including Alzheimer’s. We have synthesized derivatives of the parent molecules with substitutions on the pyridine ring (L1) or on the ‘side’ of the macrocycle (L2) designed to increase the antioxidant activity beyond that of the parent molecule in hopes of producing a molecule suitable for pharmacological testing in animal models. The lab is currently working towards substituting on the ‘bottom’ of the macrocycle (L3) to characterize and compare substitutions at each of the three positions.

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Exploring the impact that S-oxidation has on the conformation and solubility (logP) of methionine macrocycles

Type: Undergraduate
Author(s): April Cannon Chemistry & Biochemistry Liam Claton Chemistry & Biochemistry Casey Patterson-Gardner Chemistry & Biochemistry Eric Simanek Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Second Floor, Table 6, Position 1, 1:45-3:45

Macrocycles are molecules containing at least one ring composed of 12 or more atoms. Macrocyclic drugs have been used clinically for decades. Many interfere with protein-protein interactions. Therapeutic intervention requires that macrocycles remain flexible to facilitate the adoption of different conformations. Specifically, small compact hydrophobic conformations are required to cross cell membranes. The ability of a macrocycle to perform these contortions is predicted by its octonal:water partition coefficient, its so-called logP. Macrocycles (as well as small molecule drugs) that are suitable for oral delivery have a logP value <5. In this study, methionine containing macrocycles are studied. The studies commence with the synthesis of a macrocycle with a dimethylamine auxiliary group that allows for solution-phase NMR analysis. Upon formation of the macrocycle, oxidation to sulfone and sulfoxide derivatives was executed. These macrocycles are of interest because the impact that oxidation has on log P values has not been reported. Additionally, S-oxidation could change the conformation of the molecules. Synthesis beings with substitution of trichlorotriazine with BOC-hydrazine, followed by treatment with methionine in basic conditions. The final substitution of the triazine installs the auxiliary group, dimethylamine (NMR). Amidation with 1,1-diethoxypropyl amine using a peptide coupling reagent yields the monomer. Cyclization using TFA yields the macrocycle. NMR spectroscopy confirms macrocyclization and gives insight into the solution conformation of the molecule. Oxidation strategies and the results of logP analysis will be developed.

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Investigating the Effects of Variants of Unknown Significance on the Binding Interaction between BRCA1 and PALB2 for Breast Cancer Predisposition

Type: Undergraduate
Author(s): Precious Castillo Chemistry & Biochemistry Davis Martin Biology
Advisor(s): Mikaela Stewart Biology
Location: Second Floor, Table 3, Position 1, 1:45-3:45

Proper functioning of BRCA1 and PALB2 are essential in preventing tumor formation. Upon detection of DNA damage, BRCA1 binds to PALB2, leading to formation of the BRCA1-PALB2-BRCA2 DNA repair complex which is recruited to double-stranded break sites. Mutations in the genes coding for BRCA1 and PALB2 may disrupt this binding interaction, causing obstructions in DNA damage repair and increased breast cancer risk. Variants of unknown significance (VUS) found in breast cancer patients are genetic variants whose impact on the health of individuals are not yet known. Our study characterizes the effects of these VUS on the BRCA1-PALB2 binding interaction. Site-directed mutagenesis was used to generate BRCA1 and PALB2 VUS. It was found that the binding event between BRCA1 and PALB2 is enthalpic in nature and can be measured adequately via isothermal titration calorimetry (ITC). Thus, ITC was employed to identify whether the VUS disrupted binding. ITC data suggest that several PALB2 and BRCA1 VUS exhibit disruptions of the BRCA1-PALB2 binding interaction, but to varying degrees. We will share the data for variants tested thus far and emerging themes for prediction of the roles residues in both proteins play in the vital interaction.

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Effects of Solvent and Protonation on the Stereodynamics of Tri-Substituted Triazine Compounds

Type: Graduate
Author(s): Liam Claton Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Basement, Table 1, Position 3, 11:30-1:30

Barriers to rotation within triazine compounds have been previously explored by Katritzky and Birkett [1-2], but these studies have been limited to differences in the substituent groups on the triazine as well as the degree of substitution (mono, di, tri). This study explores how the barriers to rotation within triazine containing compounds are affected by solvent and protonation state. Overall, these molecules are of interest due to their wide range of applications in dendrimer and macrocycle synthesis as well as pharmaceutical drug development [3-4]. The results of this study illustrate how solvent selection can significantly impact the distribution of rotational isomers (rotamers) and how barriers to rotation can be increased by protonation of the triazine ring.

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Pyclen Macrocycle Release from Mesoporous Silica as a Drug Carrier and Impact on Amyloid Beta-Peptide Aggregation

Type: Undergraduate
Author(s): Caroline Crittell Chemistry & Biochemistry
Advisor(s): Jeff Coffer Chemistry & Biochemistry
Location: Third Floor, Table 5, Position 2, 11:30-1:30

Alzheimer’s Disease (AD) affects over 6.5 million Americans over the age of 65. Previous research links AD with the aggregation of Amyloid-beta-40 (AB40) in the brain, which creates neurotoxic plaques, causing further development of AD in the brain. A potential therapeutic mechanism in the treatment of AD is using drugs that will prevent the formation of these plaques, which is possible with Metal Chelation Therapy.
Metal ion chelation ideally stops metal ions from aiding in the aggregation of AB40. However, to deliver metal chelating agents to the brain, a drug-delivery mechanism is required that will be able to deliver this medicine across the Blood-Brain Barrier. Porous silica is a potential drug delivery material due to its particle size, high loading capacity, tunability, and biocompatibility. Along with these characteristics, porous silica can create a “sustained” release of a given drug, allowing for a slow and steady release profile, reducing the risks of medication side effects.
This project seeks to establish the optimal loading capacities of a class of potential AD therapeutic molecules known as pyclens into porous silica, each with different pyridyl moieties and chemical functionalities along the rim of the molecule. Encapsulation efficiencies measurements for these pyclen derivatives reveal loading percentages in the 10-19% range, varying by pyclen identity. Additionally, release studies monitored diffusion over time to find which pyclen molecule achieved “sustained” release. All loaded pyclen species were able to show sustained release after 20 minutes. Additional release studies of these molecules in the presence of copper (Cu2+) remain to be completed to ascertain the ability of release drugs in the presence of Cu2+ to inhibit AB40 aggregation, followed by independent assays of AB40 solubility under such conditions.

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Investigating the Effects of BRCA1 Threonine Phosphorylation on PALB2 Interaction

Type: Undergraduate
Author(s): Chloe Duvak Chemistry & Biochemistry
Advisor(s): Mikaela Stewart Chemistry & Biochemistry
Location: First Floor, Table 6, Position 2, 11:30-1:30

Two proteins, BRCA1 and PALB2 are known to aid in DNA damage repair through homologous recombination. Both proteins are phosphorylated upon DNA damage, and we hypothesize that the phosphorylation of these proteins acts as an “on switch” to allow the proteins to interact and form the DNA repair complex. To test this hypothesis, we mimicked phosphorylation on the BRCA1 protein to test the binding affinity between BRCA1 and PALB2. Phosphomimicking mutants are created by mutating an amino acid with the ability to be phosphorylated and acquire a negative charge, such as threonine (T) or serine (S), to a negatively charged amino acid, such as glutamic acid or aspartic acid. Recent research has shown that specific phosphorylation sites, such as T1394 in BRCA1 are essential to DNA damage and repair in cells. We have created a phosphomimic mutant in this specific T1394 site by mutating threonine to glutamic acid. We are currently measuring the effect that this mutation has on the ability of BRCA1 to bind to PALB2 in vitro. The obtained data will reveal whether phosphorylation has an impact on the interaction between these two proteins or not.

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Impact of Selected Ionic Liquids on the Properties of Metal Halide Perovskites

Type: Graduate
Author(s): Maegyn Grubbs Chemistry & Biochemistry Sergei Dzyuba Chemistry & Biochemistry
Advisor(s): Jeff Coffer Chemistry & Biochemistry
Location: Third Floor, Table 10, Position 1, 11:30-1:30

Metal-halide perovskites are crystalline materials that work as a semiconductor in both Light Emitting Diodes (LEDs) and solar cells. In general, perovskites possess the formula ABX3. For this project, the A site is an organic molecule such as Methylammonium (MA), the B site is Lead, and the X site is Bromide. While perovskites are easily fabricated, their crystal size and number of defects present are challenging to control. Defects cause LEDs to be less stable and/or less photoluminescent (bright) and cause solar cells to be less efficient at converting light to energy. One approach to reduce the number of defects is to use ionic liquids during perovskite formation. Ionic liquids are compounds made of ions in the liquid state due to a low melting temperature. They can be added to the perovskite precursor solution to slow down the crystallization process so that fewer defects are created. The goal of this project is to create new metal halide perovskites in the presence of selected ionic liquids, evaluate their structure and photophysical properties, with the long-term goal of creating new LEDs that are both stable and efficient.

In this project, cetyl-ionic liquids (cetyl meaning 16 carbon chains) were investigated for their effects on perovskite structure and light emission. The three ionic liquids were investigated: [C16-mim]Br (referred to as "IL1"), [C16-py]Br ("IL2"), and [C16-C1pyrr]Br ("IL3"). Variations on the addition method of ionic liquids to the perovskite precursor were studied as well. It was hypothesized that the inclusion of cetyl-ionic liquids will protect the perovskite films from the environment (increasing stability) by providing a hydrophobic layer on the surface and will improve the electronic properties by filling in pinholes that cause defects. It is found that perovskite films with IL3 are more photoluminescent than the perovskite films formed with IL1, IL2, or no IL (control). Preliminary experiments varying the addition method of IL3 during film formation have shown that the perovskite films are brightest when IL3 is added to both the precursor and the antisolvent layers at the beginning of the fabrication process. These results, along with detailed structural characterization of a given perovskite film, will be discussed in this presentation.

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Models for the Next Generation of Drugs: Design, Synthesis, and Conformational Analysis of a 26- Atom Macrocycle

Type: Undergraduate
Author(s): Nathan Kebler Biology Alex Menke Chemistry & Biochemistry Eric Simanek Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Basement, Table 3, Position 3, 11:30-1:30

To fight disease, pharmaceutical companies have historically prepared small molecules designed to interfere with specific sites on proteins (enzymes) to prevent chemical reactions from taking place. However, a second paradigm for interfering with proteins has gone largely unexplored--blocking protein-protein interactions. To accomplish the latter, large molecules are needed to bind to large areas on the protein target. However, large molecules present additional challenges. Typically, they are hard to synthesize, not orally available, and typically cannot cross cell membranes. Nature has designed large molecules like cyclosporin that should not work as drugs based on our current understanding. Despite its size, cyclosporin is orally available and can cross cell membranes. This research explores the design, synthesis, and conformational analysis of similar large ring-shaped molecules, so-called macrocycles. In this work, we are increasing the size of the ring-shaped molecule. By increasing the size of the ring-shaped molecule and varying the amino acid (in this case, valine), we are expanding the possible ways in which our macrocycle may interfere with protein-protein interactions. Here, a 26-atom macrocycle is reported. 1H NMR spectroscopy reveals a protonated molecule that is highly dynamic which has access to a beta-sheet conformation.

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The effects of protonation and hydrogen bonding on templating efficient macrocyclization

Type: Undergraduate
Author(s): Lola Kouretas Chemistry & Biochemistry Benjamin Janesko Chemistry & Biochemistry Alexander Menke Chemistry & Biochemistry
Advisor(s): Eric E. Simanek Chemistry & Biochemistry
Location: Third Floor, Table 7, Position 2, 1:45-3:45

Macrocyclic drugs adopt multiple conformations--a behavior referred to as chameleonicity--to navigate hydrophobic cellular membranes and aqueous intracellular environments. The rules for understanding this behavior are beginning to emerge through studying existing drugs and the synthesis of model systems. Historically, one challenge to macrocycle synthesis is low yield reactions. To this end, dynamic covalent chemistry has been explored. Here, macrocycles are afforded readily by dimerization with the formation of two hydrazones.

The efficiency of the macrocyclization reaction led to the hypothesis that upon formation of the first hydrazone, the acyclic intermediate was preorganized to place the hydrazine and acetal in close proximity thereby reducing the likelihood of oligomeric or polymeric products. The preorganization could result from a network of hydrogen bonds. Moreover, in an acidic environment, wherein the triazine ring is protonated, the opportunity for bifurcated hydrogen bonds emerge. Computation has been used to identify sites for protonation and the energetic contributions of hydrogen bonding.

To explore templating and the role of protonation in the formation of hydrogen bonds, model systems were prepared that emulate ‘half’ of the macrocycle. The acetylated aminoacetal offers a well-resolved NMR spectrum. In contrast, hindered rotation about the triazine-N bond leads to a mixture of rotamers in the hydrazine component. However, upon condensation, a single rotamer is observed and resonances corresponding to the hydrogen bonded protons emerge downfield between 7-12 ppm. Computation provides estimates of the energetic contribution of the bifurcated hydrogen bond as well as the hydrogen bond formed in the absence of protonation. The results of titration and variable temperature NMR experiments will also be described.

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Exploration of Radical Scavenging Reactivity in Substituted Pyridinophane Ligands for Alzheimer's Disease Therapeutics

Type: Undergraduate
Author(s): Christina Mantsorov Chemistry & Biochemistry David Freire Chemistry & Biochemistry Magy Mekhail Chemistry & Biochemistry Kristof Pota Chemistry & Biochemistry Katherine Smith Chemistry & Biochemistry
Advisor(s): Kayla Green Chemistry & Biochemistry
Location: First Floor, Table 5, Position 2, 11:30-1:30

The mis-regulation of reactive oxygen species and transition metal ions contributes to the onset of Alzheimer’s Disease. Reactive oxygen species are a natural byproduct of metal redox cycling that occurs within the body and are important in processes like homeostasis and various pathways of cell signaling. Two series of pyridinophane ligands were produced and evaluated for the ability to target the molecular features of Alzheimer’s Disease. The functionalized pyridinophanes were chosen to analyze their blood-brain barrier permeability and radical scavenging ability when included within a molecular scaffold. Preliminary results with the DPPH assay indicated a significant increase in radical scavenging activity for ligands containing electron-donating substitutions in comparison to the parent ligands. These results warrant further exploration into the mechanism of the activity observed.

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Building the Petro-Informatics Chemical Structure Database

Type: Undergraduate
Author(s): Sydney Mazat Chemistry & Biochemistry
Advisor(s): Benjamin Janesko Chemistry & Biochemistry
Location: Third Floor, Table 3, Position 1, 11:30-1:30

Petroleum crude oil, unconventional crudes, and renewable bio-crudes are essential materials in our everyday lives. They fuel vehicles, heat buildings, provide electricity, and are used to produce a multitude of other materials, such as plastics and solvents. Crudes are highly complex chemical mixtures, estimated to contain between 100,000 and 100,000,000,000,000,000 unique molecules. Since 2015, single-molecule imaging has visualized hundreds of chemical structures, and historical literature has published thousands of proposed structures. This project builds an open database populated with published crude structures enabling data-driven analysis of these structures, and detailed workflows, allowing for easy future insertion of new molecules into the database. This database can be used to make calculations and predict characteristics of molecules, such as viscosity, density, and reactivity, which are all critical in refinery plants, transportation, and usage of these fuels. Performing queries on the molecules in the database to filter for specific characteristics allows scientists to develop more successful experiments by refining their hypotheses to account for the query results displaying possibilities of their desired outcome.  

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Opening the Door on Molecular Hinges

Type: Undergraduate
Author(s): Joseph Mellberg Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: First Floor, Table 2, Position 1, 11:30-1:30

This research aims to understand how to design and control molecular hinges. The molecular hinges of interest are nano-sized equivalents of door hinges. Such hinges could find applications in new materials or the design of new drugs.

The foundation for this research was the observation that a large, ring-shaped molecule - a so-called macrocycle – prepared by a colleague folded and unfolded rapidly at room temperature. Two research questions arose from this observation: was the hinge behavior unique to this molecule, and could the hinging rate be controlled?

Addressing these questions required the three-step synthesis of a related macrocycle. This new molecule had groups equivalent to putting grit around the hinge's pin. The difference in the rate of hinging motion due to the addition of these groups was observed using a technique called variable temperature NMR spectroscopy.

The results of this work revealed that hinging is a general phenomenon for some of these macrocycles. Second, the 'molecular dirt' designed into this new hinge reduced the rate of hinge motion from 2000 times per second to 20 times per second.

This work is being written up for communication to the Journal of the American Chemical Society based on the novelty of this molecular device and the scientific community's interest in molecular machines.

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How Tacos and Tortillas Can Shape Antibiotics

Type: Graduate
Author(s): Alexander Menke Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Basement, Table 6, Position 1, 11:30-1:30

Dating back to 1550 B.C., ancient civilizations used moldy bread and medicinal soil to treat infections and wounds. Today, antibiotics are commonly used to treat bacterial infections. Salvarsan, the first antibiotic, was developed in 1910, followed by penicillin in the late 1920s. However, the widespread use of antibiotics and limited research has resulted in the emergence of antimicrobial resistance, posing a global threat. To address this, developing new antibiotics is crucial. Vancomycin, a potent antibiotic isolated in 1955 and synthesized in the late 1990s, is a target for this purpose. Despite its effectiveness, vancomycin is challenging to produce, with yields not exceeding 5%. Thus, this project aims to create a structure in four steps, with a yield greater than 50% that resembles vancomycin’s iconic 3-D bowl shape.

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Conjugating Folic Acid to Platinum Nanocrystals on Silicon Nanotubes for targeting breast cancer.

Type: Graduate
Author(s): Leonardo Ojeda Hernandez Chemistry & Biochemistry
Advisor(s): Jeffery Coffer Chemistry & Biochemistry Giridhar Akkaraju Biology
Location: Basement, Table 11, Position 2, 1:45-3:45

Platinum compounds play an important role as anticancer agents. Their ability to bind to DNA in the nucleus (by a process known as intercalation within DNA base pairs) result in DNA damage and cell death. Unfortunately, these platinum-containing compounds lack specificity toward cancer cells and attack normal healthy cells that results in significant side effects as a consequence (loss of hair, nausea, among others).
Our group has developed a method to incorporate platinum on the surface of our silicon Nanotubes using (3-Aminopropyl) triethoxysilane (APTES) as a functional arm to the Nanotubes. The Silicon nanotubes have attracted great attention in applications relevant to diagnosis and therapy, owing in part to its biocompatibility and biodegradability in cells.
Once inside the cell, platinum is released slowly, thus allowing an interaction with DNA. Our previous results using this technology showed significant toxicity on a type of cancer cell known as HeLa. While these findings are promising, specificity has not yet been achieved.
Cancer activates signaling pathways that translates on overexpression of specific proteins/receptors. Particularly, folate receptors (FR) are present in 90-98% of ovarian, prostate, uterus, breast, as well as some adenocarcinomas. FR expression is very limited in normal cells and generally not accessible to blood flow which makes it a suitable and promising system to target cancer. These receptors are glycopolypeptides that present high affinity for folic acid (FA).
A viable strategy has been identified, involving the conjugation of a molecule known as glutathione to act as a linker to the surface of the silicon-based platinum nanoparticles through N-Hydroxysuccinimide (NHS) activation, followed by substitution with folic acid.
The cellular evaluation of this material shown high cytotoxicity against Hela cells and selectivity, in compare with material without Folate.

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Activity-Structure Relationship: Partition Coefficients of Triazine Macrocycles Predicts their Conformation

Type: Graduate
Author(s): Casey Patterson-Gardner Chemistry & Biochemistry April Cannon Chemistry & Biochemistry Gretchen Pavelich Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Third Floor, Table 3, Position 2, 11:30-1:30

Peptidomimetic macrocycles are of ever-growing interest to the field of pharmacology as candidates for inhibiting supposed "undruggable" sites (such as protein-protein interactions). An important property of pharmacophores within drug development is the partition coefficient (often expressed as logP or logD), which measures the ability of a molecule to partition between aqueous and organic media, effectively expressing the ability for a drug to diffuse into a cell from the bloodstream. Our group has previously synthesized several amino acid-containing triazine macrocycles through facile three-step procedure yielding folded, sometimes dynamic, macrocycles in good yields. With twelve macrocycles, a trend in logD values has emerged, allowing for the rapid prediction of the macrocyclic conformation per its respective logD values. Each macrocycle is folded, but the extent of triazine-triazine overlap, side chain van der Waals interactions, and shielding of its central proton is reflected in the divergence of the macrocycle's logD from a central trendline. The ability to predict the macrocycle's logD values via additive, atomistic, algorithms is also shown to reveal this divergent trend. Structures of these triazine macrocycles were elucidated through proton and nOesy/rOesy NMR.

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Showing Big Pharma Where to Look for New Drugs: Developing New Models for Determining whether Large Molecules are Orally Available

Type: Undergraduate
Author(s): Gretchen Pavelich Chemistry & Biochemistry Casey Patterson-Gardner Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Third Floor, Table 4, Position 2, 11:30-1:30

In the world of drugs, the chemical property that is most important is logP, the predictor of whether a drug can be taken orally and cross the cell membrane. Pharmaceutical companies will not explore molecules with logPs that are outside the ideal range. But what if predictions are wrong? The rules for predicting logP are based on small molecules, but the industry is moving towards large molecule drugs. This poster looks at synthesizing models of large molecule drugs (ring-shaped molecules called macrocycles) to determine if the logP of large molecules can be predicted. Synthesis of a hydrophobic macrocycle shows that the industry predicted logP failed. New prediction methods are needed. To develop these methods, additional macrocycles were made to serve as models for prediction. These molecules also allow us to explore another avenue in drug design challenge another paradigm in drug discovery. Pharmaceutical companies avoid hydrophilic functional groups because of ill predictions about logP. Combining these hydrophilic groups with predictable hydrophobic groups will make the molecule's logP acceptable. That is, by design, the undesirable hydrophilic group is balanced with the desirable hydrophobic group to bring polar groups through the membrane. Overall, the work will allow for a wider range of molecules to be considered for potential drug design.

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Computational Prediction of Isoelectric Point (pI) and Acidity (pKa) of Pyridinophane Macrocycle Derivatives using Density Functional Theory

Type: Undergraduate
Author(s): Minh Nhat Pham Chemistry & Biochemistry Benjamin Janesko Chemistry & Biochemistry
Advisor(s): Benjamin Janesko Chemistry & Biochemistry
Location: Third Floor, Table 7, Position 1, 11:30-1:30

Oxidative stress occurs when there is an imbalance between free radical activities, including those of reactive oxygen species (ROS), and the body’s natural antioxidant mechanism. To help restore this balance, the Green research group at TCU has developed tetradentate pyridine-containing cyclen macrocycles capable of simultaneously carrying out various modes of antioxidant activities. As drug candidates , these molecules need to be further modified with different functional groups to fine-tune their activities and pharmacological properties, resulting in a large library of up to hundreds of derivative structures. Isoelectric point (pI) and acidity (pKa) play a vital role in assessing the membrane permeability of these molecules. Given the size of the library, experimental determination of these values is an unnecessarily time-consuming endeavor. Using the state-of-the-art Density Functional Theory (DFT), this project aims to 1) show how pI values of any molecules in this library can be predicted with reference to a desired value and 2) predict the pKa of different acidic sites on these multifunctional molecules. This can potentially shed light on the effects of covalent modifications on pI and pKa values, and with further optimizations, can be applied to a virtual screening protocol for any libraries of drug candidates.

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Effect of HEPES on Lysozyme Crystallization from Metastable Protein-Rich Droplets

Type: Undergraduate
Author(s): Jenny Pham Chemistry & Biochemistry Shamberia Thomas Chemistry & Biochemistry
Advisor(s): Onofrio Annunziata Chemistry & Biochemistry
Location: Second Floor, Table 7, Position 1, 11:30-1:30

Protein crystallization is regarded as a more economically sustainable strategy for achieving protein purification compared to traditional downstream processing chromatography. However, protein crystallization is not a well understood process and still relies on empirical protocols. This work examines the rational design of protein crystallization for lysozyme, a model protein, by exploiting the formation of metastable protein-rich droplets by liquid-liquid phase separation (LLPS). Specifically, sodium chloride, which is a salting-out agent, is used to induce LLPS, while 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) is a salting-in agent used to modulate LLPS conditions. It was found that HEPES enhances protein crystallization from protein-rich droplets. This effect can be explained by examining the relative shift of the LLPS boundary with respect to crystal solubility in the temperature-composition phase diagram. This work suggests that LLPS-mediated protein crystallization may be enhanced in the presence of salting-in agents.

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Rings of Power: Controlling SOD Mimic Activity with Pyridinophane Modifications

Type: Graduate
Author(s): Katherine Smith Chemistry & Biochemistry Cameron Bowers Biology David M. Freire Chemistry & Biochemistry Magy Mekhail Chemistry & Biochemistry Timothy M. Schwartz Chemistry & Biochemistry
Advisor(s): Kayla Green Chemistry & Biochemistry
Location: Second Floor, Table 8, Position 1, 1:45-3:45

Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) in the body and is
a key player in many maladies, including neurological diseases like Parkinson’s and Alzheimer’s disease.
Superoxide dismutase (SOD) metalloenzymess are capable of transforming the common ROS molecule
superoxide (O2) into less toxic species such as H2O or O2, thus protecting the body from harmful reactions of
superoxide. Synthetic metal complexes have shown promise as SOD mimics and can be effective alternatives
to therapeutic dosing of SOD enzyme for oxidative stress. In this work, we present a series of 12-membered
tetra-aza pyridinophanes (Py2N2) and the corresponding copper complexes with substitutions on the 4-position
of the pyridine ring. The SOD functional mimic capabilities of the Cu[Py2N2]Cl series were explored using a
UV-Visible visible spectrophotometric assay. Spectroscopic, potentiometric, and crystallographic methods were
used to explore how the electronic nature of the 4-position substitution affects the electronics of the overall
complex, and the SOD biomimetic activity of each complex’s activity as a SOD mimic. This work is an initial
step toward developing these Cu[Py2N2]Cl complexes as potential therapeutics for neurological diseases by
mimicking SOD’s capabilities and protecting the body from oxidative stress.

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Green, Sustainable, and Efficient Syntheses of Squaraine Dyes For Biomedical and Energy-Related Applications

Type: Graduate
Author(s): Daniel Ta Chemistry & Biochemistry Jeanne Favret Chemistry & Biochemistry Ernesto Rodriguez Chemistry & Biochemistry
Advisor(s): Sergei Dzyuba Chemistry & Biochemistry
Location: Second Floor, Table 5, Position 1, 11:30-1:30

Squaraine dyes are a class of small luminescent molecules with diverse applications in physical sciences, medicine, and engineering. Although widely used, the current synthetic approaches are neither modular nor environmentally friendly. Therefore, this poster will present our efforts to develop facile, diverse, and efficient synthetic methods for squaraine dyes, based on green chemistry and sustainability principles.

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