Predicting pKas of flexible polybasic pyclen derivatives: A pKa challenge

Type: Undergraduate
Author(s): Tatum Harvey Chemistry & Biochemistry
Advisor(s): Benjamin Janesko Chemistry & Biochemistry Kayla Green Chemistry & Biochemistry
Location: Third Floor, Table 2, Position 1, 1:45-3:45

Predicting pKas is an outstanding challenge in computational chemistry. The Green group
at TCU is working to develop a library of pyclen derivatives that can successfully reduce oxidative
stress within the brain of people afflicted with neurodegenerative diseases1. Predicting the various
pKas of these flexible molecules, which are charged at neutral pH, challenges conventional
approaches to predicting pKas. For each pyclen derivative, we combine an extensive survey of
protonation site isomers, with conformational sampling using the CREST package2, DFT
calculations with continuum solvent models, followed by a linear fit to correct the solvent models
limitations for calculating energy of highly charged species. We can predict three to five measured
pKa values for each pyclen derivative with a RMSD of 0.9 pKa units, which is competitive with
the best-physics based method in the SAMPL6 blind challenge for the first pKa3. We are pushing
the boundaries of computational chemistry and its abilities to predict multiple pKas of flexible
molecules.

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

Type: Undergraduate
Author(s):
Advisor(s):
Location: First Floor, Table 4, Position 1, 1:45-3:45

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.

Implication of Steric Congestion on Sheet Formation: 26-Atom Macrocycles

Type: Undergraduate
Author(s): Lola Kouretas Chemistry & Biochemistry Luke Homfeldt Chemistry & Biochemistry Alex Menke Chemistry & Biochemistry
Advisor(s): Eric Simanek Chemistry & Biochemistry
Location: Second Floor, Table 1, Position 1, 1:45-3:45

Molecular engineering of larger macrocyclic compounds offers new avenues to disrupt protein-protein interfaces and potentially halt pathways that lead to neurodegenerative diseases, such as Alzheimer’s. The hallmark of Alzheimer’s disease involves the aggregation of so-called amyloid peptides that exhibit characteristic β-sheet structures. Thus, designing macrocycles that structurally/topologically mimic β-sheets should enhance the affinity of these macrocycles towards the amyloid aggregates and lead to rational design of more advanced scaffolds with superior structures. This will potentially present opportunities to interrogate protein-protein interactions, thus preventing amyloid plaque formation.

This work will describe the synthesis of structurally and functionally-diverse macrocyclic scaffolds containing leucine and isoleucine to understand the factors that contribute to β-sheet formation. Here, 26-atom macrocycles prepared in three steps will be described. Using a triazine core, a protected hydrazine group, and an amino acid constitute the base acid. In the second step the addition of an acetal of variable length forms the monomer. Acetals ranging from 2-4 carbons can be used to yield rings of 22-28 atoms. Previous work proves acetal length dictates morphology; three-carbon acetals demonstrate folded conformations and five-carbon acetals yield crinkled b-sheets. Four-carbon acetals yield the flattened b-sheets described here. Treatment with acid leads to dimerization in very high yields. Varying the amino acid choice can give way to synthesis of different homodimers and heterodimers.

These studies also address the optimization of the macrocyclization step. Early results indicate that a >300x reduction in the time of reaction (from 7 days to 30 min) might be realized. NMR spectroscopy provides confirmation of synthesis and 2D-NMR techniques offer opportunities to probe solution structure more efficiently.

Fabrication Process And Efficiency Analysis Of Organic Light-Emitting Diodes (OLEDs)

Type: Undergraduate
Author(s): Nhu Le Engineering
Advisor(s): Jeffery Coffer Chemistry & Biochemistry
Location: Second Floor, Table 1, Position 3, 1:45-3:45

Display technology is one of the industries of great significance, providing benefits for consumers with applications such as smartphones, televisions, and computer monitors. One of the current research topics in this industry of extensive interest is the development of new organic light-emitting diodes or OLEDs.

While such devices are common, fundamental challenges remain. Three pressing needs are: (1) longer device lifetimes, (2) lower fabrication costs, and (3) better control over emission color for ultrahigh definition displays and white-light lighting. Today, high-quality displays are built using high-vacuum deposition of molecular precursors, an expensive method unsuitable for ultra-large displays. Methods that rely on spin coating or printing of solutions of such precursors are far more economical, but present fabrication challenges of their own.

Our goal here is to improve device function and stability in OLEDs through simple solution-based routes with innovative fluorescent structures known as perovskites as building blocks. Ideally these new OLEDs will perform well at low voltage ranges and maintain good light emission intensity, as evaluated using techniques known as photoluminescence and electroluminescence spectroscopies.

In this research project, single-layer OLED and three-layer OLED devices are analyzed. Single-layer OLED devices consist of the substrate, anode, emissive layer, and cathode. Fluorine-doped Tin Oxide (FTO)/glass and Indium Tin Oxide (ITO)/plastic are the main substrates used, acting as anode. Ga-In eutectic, Silver Nanowire (AgNW), and Silver Epoxy are used as the interconnect / cathode layer to the emissive layer. To fabricate a three-layer OLED, the electron transport layer (ETL) is added between the cathode and emissive layer and a hole transport layer (HTL) added between emissive layer and anode, both to ideally improve energetics of electron/hole injection to the emissive layer. In our experiments, a species known as PEDOT:PSS is typically the hole transport layer and for the electron transport layer, we use ZnO or a mixture of ZnO and polyethylenimine.

The most success to date has been achieved with [Ru(bpy)3]2+ as the active emitting species in a thin polymer matrix referred to poly-vinylalcohol (PVA). Our current results show that the photoluminescence spectroscopy intensities were relatively high while the electroluminescence needs to be improved. The best result was recorded with the single-layer red OLED, which is made of FTO, [Ru(bpy)3]2+, and Ga-In eutectic. Visible light emission at low voltages from 3.5V-7V could be observed with the unaided eye under these conditions.

Bridging Theory and Practice Enhancing Drug Design Through Molecular Simulations and Solvent Stability Analysis

Type: Undergraduate
Author(s): Alejandro Munoz Chemistry & Biochemistry
Advisor(s): Benjamin Janesko Chemistry & Biochemistry
Location: Second Floor, Table 2, Position 3, 1:45-3:45