Structural Biology Commons^™

Decoding The Allosteric Grammar Of Protein Kinases: A Dual-Stream Framework Integrating Protein Language Models And Energy Landscape Frustration Analysis, Will Gatlin, Max Ludwick, Lucas Turano, Brandon Foley, Kamila Riedlova, Vít Škrhák, Marian Novotný, David Hoksza, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The spatial and energetic encoding of allosteric regulatory sites remains a major challenge in structural biology, frequently representing a “blind spot” for sequence-based artificial intelligence (AI) models. We present a protein language model (PLM)-guided approach complemented by the energy landscape frustration analysis as a dual-stream framework to investigate the relationship between AI prediction of binding sites and biophysical organization of regulatory pockets across the human kinome. By probing a fine-tuned residue-level PLM classifier across 453 kinase structures, a clear performance gap is discovered between highly predictable orthosteric pockets (Types I, I.5, and II) and poorly resolved distal allosteric sites (Type …

Membrane Organization Of Rheb And Rhoa: Roles In Function And Allosteric Druggability, Chase M. Hutchins

Dissertations and Theses (Open Access)

Small GTPases of the Ras superfamily are membrane-bound molecular switches that regulate nearly all major cellular processes, and their dysregulation drives cancers, neurological disorders, and metabolic diseases. While anchored to cellular membranes, the catalytic domains of small GTPases undergo orientation dynamics, adopting distinct configurations that can occlude or expose effector-binding surfaces and modulate signaling output. These dynamics have been characterized in the Ras oncoproteins, but whether they extend across the superfamily and influence allosteric druggability has remained unknown.

In this dissertation, I address these questions through Rheb and RhoA, two small GTPases with complementary differences in subfamily lineage, membrane localization, …

Exploring The Limitations Of Substrate Scope In Dimethylallyltryptophan Synthases, Evan T. Miller

Theses and Dissertations--Pharmacy

Natural products (NPs), are the largest source of bioactive compounds in Nature, and are essential to the treatment of human disease. Nearly 50% of drugs approved for use from 1981 to 2019 owe some aspect of their development to NPs, either in terms of their structure, pharmacophore, or mechanism of action. However, NPs are difficult to structurally optimize. Chemoenzymatic methods for NP derivatization have been increasingly seen as practical alternatives to traditional synthetic methods. Prenyltransferases (PTs) are involved in the primary and secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically …

Tree Story, Jia Hu

Masters Theses

What is Nature?

Nature is a system of intelligence. It means designing for efficiency—often by learning from strategies that have evolved over time. In my research, I use patterns to interpret and decode nature.

To explore nature, I began with the red cedar tree, aiming to simulate and predict its growth patterns—forms shaped by both internal biology and external forces. By analyzing its geometry, I sought to understand how trees embody the dynamic relationship between organism and environment. These patterns reveal the adaptive logic of life.

Patterns are central to understanding nature. While tree geometry may appear chaotic, it follows …

Characterization Of Sars-Cov-2 Replication And Transcription Complexes Via Structural And Evolutionary Approaches, Amelie Ghirardo, Ben Shabatian, Avishai Aghelian, Kyle Tau, Eleonora Gianti

Undergraduate Research

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused around 700M cases and over 7M COVID-19-related deaths recorded worldwide (World Health Organization, March 2025). Aiming to effectively combat this and other disease-causing Coronaviruses (CoV), unprecedented research efforts led to the development of new vaccines and antiviral therapies. Due to emergence of variants of concern (VOCs) with increased transmissibility, immune evasion from vaccination, and potential to resist the available treatments, SARS-CoV-2 continues to represent a major threat to global health. Hence, there is a pressing need to discover new antivirals with broad-spectrum efficacy against multiple SARS-CoV-2 variants and related CoVs. This project …

Sequence Conservation Of Suppressor Of Ikk Epsilon Phosphorylation Sites, Kaydence M. Isaacs

Undergraduate Honors Theses

Suppressor of IKK epsilon (SIKE) is a protein that is implicated in immune response signaling pathways. SIKE interaction networks suggest roles in cell motility and macromolecular complexes mediating kinase/phosphatase activity. In this project, we aim to better understand the function of SIKE by analyzing amino acid sequences across different species. In human SIKE, viral infection leads to phosphorylation of SIKE at defined serine residues. Comparing SIKE sequences, and specifically these phosphorylation sites, allows us to discover its ancestral connections to innate immune function. This has particular applications in bridging the evolutionary gap between fungi and metazoa SIKE sequences. Multiple sequence …

Bloom: Behavioral Learning And Outcome Observation In Microbes, Sean Sarwar Haque, Luke Compton Wharton, Ming Lin, Razvan Voicu

Symposium of Student Scholars

Understanding how pathogens respond to physical changes in their environment is crucial for developing effective treatments and preventative measures. Current research often relies on static models or experimental data that either fail to capture the dynamic interactions within cellular environments or are not generalizable to other types of pathogens. This project aims to address this gap by creating a comprehensive cell simulation that models pathogens and their response to chemical, physical, and physiological changes. The proposed solution is a simulation that integrates biological data and computational modeling to replicate the behavior of pathogens in real time as they are affected …

The Role Of Secondary And Tertiary Structure In The Cap-Independent Translation Of Fgf-9 And Hif-1-Alpha, Amanda Michelle Whittaker

Dissertations, Theses, and Capstone Projects

Under normoxic conditions, eukaryotes initiate translation of RNA through eIF4E recognition of the 5’ cap. However, under cellular stress, eukaryotic translation must be initiated through a 4E-independent, or “cap-independent” mechanism, involving eukaryotic initiation factor 4G (eIF4G) binding directly to the 5’ untranslated regions (5’ UTR) of the RNA. eIF4G binding then recruits the ribosome to the transcript. While this mechanism is useful for translation of apoptotic transcripts and transcripts involved in cell survival, cap-independent translation is also utilized by oncogenic RNA for tumorigenesis. Previous work by our lab and others has categorized this recruitment and initiation mechanism as either internal-ribosome-entry-site …

Development Of Cyan And Blue Thermostable Fluorescent Proteins: Characterization And Structural Analysis, Acacia J. Jurkowski

Graduate Theses/Dissertations

Fluorescent proteins are commonly used as cell markers in living organisms. Modifications by mutation can be used to improve the qualities of these proteins including fluorescence, thermostability, pH stability, and chemical stability. The goal of this project is to use mutagenesis to improve the fluorescence of thermostable cyan and blue proteins derived from the thermal green protein (TGP). The first cyan protein developed by the DeVore lab (CTP 0.0) shifted the fluorescence to cyan but decreased the quantum yield (Φ_F) to 0.056. Further mutations were incorporated to increase the quantum yield through incorporating hydrogen bonding interactions to the …

Technological Development Of In-Cell Nmr: Microfluidic, Metabolomic, And Fluxomic Approaches, Nicholas Sciolino

Electronic Theses & Dissertations (2024 - present)

In the fields of structural biology, metabolomics, and fluxomics, there is a driving, technique-based concern when it comes to high-resolution spectrometry and its marriage to biological and physiological relevance. Sample preparation often involves cellular perturbation, lysate separation schemes, combinations with non-biological reagents, and timeline slack. Conceptually, the farther we get from the cell, the greater the potential disparity between what exists in vivo and our in vitro manipulations. This is particularly true when seeking to collect data on transfected targets of interest, and on sensitive metabolic equilibria that occur on the order of minutes. The question remains: if we are …

Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

D101n: A Unique And Ill-Understood Familial Als-Related Sod1 Mutant, Analisa Lott

Honors Program Theses and Research Projects

Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, with 90% of documented cases considered sporadic and about 10% showing a hereditary link; such cases are deemed as familial ALS (fALS). Superoxide dismutase (SOD), a copper-zinc binding enzyme that protects cells from damaging free radicals, has been linked to fALS with certain toxic gain of function mutations, such as the D101N mutant. The human SOD1 D101N mutant has been shown to be associated with rapidly progressing neurodegeneration yet is less prone to aggregation than similar mutants, but its deviation from wild-type (WT) SOD1 remains misunderstood.

Objective: Although the D101N …

Cross-Interactions Of Amyloid Proteins: Implications For Aggregation Dynamics And Disease Pathology, Zhiyuan Song

All Dissertations

Amyloid aggregation is a pervasive form of protein misfolding implicated in the pathology of several prominent human diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and type 2 diabetes (T2D). These diseases are marked by the accumulation of amyloid fibrils and toxic oligomers, which are highly dynamic and heterogeneous, posing challenges for understanding their roles in disease progression. Despite significant advances in the diagnosis and management of these conditions, no definitive cure is available. We investigate amyloid aggregation and cross-seeding, with a focus on amyloid-beta (Aβ), tau, alpha-synuclein (αS), and human islet amyloid polypeptide (IAPP) through discrete molecular dynamics (DMD) …

"Deep Learning For Microscope Image Denoising", Nasreen Buhn, Sriya Adunur, Guy Hagen, Jonathan Ventura

College of Engineering Summer Undergraduate Research Program

In order to avoid damaging live cells, optical microscope imaging must be conducted under low-excitation light intensity and/or short exposure times, resulting in low signal-to-noise ratios (SNR). Deep learning methods offer an effective solution for removing microscope noise, utilizing algorithms that are able to reconstruct finer features in low SNR images. This research explores the denoising capability of several deep learning methods based on PSNR and SSIM. Tested methods include traditional approaches (BMED), supervised learning (CARE and Restormer), and unsupervised methods (Noise2Fast, N2V, SSD-Unsupervised, and SASSID). The Restormer model, which employs an encoder-decoder transformer architecture and progressive learning, stood out …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Mathematical Modeling Of Microscale Biology In Polyelectrolyte Brushes, William J. Ceely

CGU Theses & Dissertations

Biological macromolecules including nucleic acids, proteins, and glycosaminoglycans are typically anionic and can span domains of up to hundreds of nanometers and even micron length scales. The structures exist in crowded environments that are dominated by multivalent electrostatic interactions that can be modeled using mean-field continuum approaches that represent underlying molecular nanoscale biophysics. In this thesis, we develop such models for polyelectrolyte brushes using both steady state modified Poisson-Boltzmann models and transient modified Poisson-Nernst-Planck models that incorporate important ion-specific (Hofmeister) effects. The transient model enables observation of the relative physical effects as an initial non-equilibrium state relaxes to the steady …

Langevin Dynamic Models For Smfret Dynamic Shift, David Frost, Keisha Cook Dr, Hugo Sanabria Dr

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Optimization And Application Of Graph Neural Networks, Shuo Zhang

Dissertations, Theses, and Capstone Projects

Graph Neural Networks (GNNs) are widely recognized for their potential in learning from graph-structured data and solving complex problems. However, optimal performance and applicability of GNNs have been an open-ended challenge. This dissertation presents a series of substantial advances addressing this problem. First, we investigate attention-based GNNs, revealing a critical shortcoming: their ignorance of cardinality information that impacts their discriminative power. To rectify this, we propose Cardinality Preserved Attention (CPA) models that can be applied to any attention-based GNNs, which exhibit a marked improvement in performance. Next, we introduce the Directional Node Pair (DNP) descriptor and the Robust Molecular Graph …

Exploring Topological Phonons In Different Length Scales: Microtubules And Acoustic Metamaterials, Ssu-Ying Chen

Dissertations

The topological concepts of electronic states have been extended to phononic systems, leading to the prediction of topological phonons in a variety of materials. These phonons play a crucial role in determining material properties such as thermal conductivity, thermoelectricity, superconductivity, and specific heat. The objective of this dissertation is to investigate the role of topological phonons at different length scales.

Firstly, the acoustic resonator properties of tubulin proteins, which form microtubules, will be explored The microtubule has been proposed as an analog of a topological phononic insulator due to its unique properties. One key characteristic of topological materials is the …

The Metabolomics Workbench File Status Website: A Metadata Repository Promoting Fair Principles Of Metabolomics Data, Christian D. Powell, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

Background: An updated version of the mwtab Python package for programmatic access to the Metabolomics Workbench (MetabolomicsWB) data repository was released at the beginning of 2021. Along with updating the package to match the changes to MetabolomicsWB’s ‘mwTab’ file format specification and enhancing the package’s functionality, the included validation facilities were used to detect and catalog file inconsistencies and errors across all publicly available datasets in MetabolomicsWB.

Results: The MetabolomicsWB File Status website was developed to provide continuous validation of MetabolomicsWB data files and a useful interface to all found inconsistencies and errors. This list of detectable issues/errors include format …

Modeling Accuracy Matters: Aligning Molecular Dynamics With 2d Nmr Derived Noe Restraints, Milan Patel

Honors Scholar Theses

Among structural biology techniques, Nuclear Magnetic Resonance (NMR) provides a holistic view of structure that is close to protein structure in situ. Namely, NMR imaging allows for the solution state of the protein to be observed, derived from Nuclear Overhauser Effect restraints (NOEs). NOEs are a distance range in which hydrogen pairs are observed to stay within range of, and therefore experimental data which computational models can be compared against. To that end, we investigated the effects of adding the NOE restraints as distance restraints in Molecular Dynamics (MD) simulations on the 24 residue HP24stab derived villin headpiece subdomain to …

Determination Of Cadmium Uptake In Crassostrea Virginica Shell Under Controlled Conditions, Joseph John Pavelites Ii

Graduate Theses and Dissertations (2019 - present)

The objective of this thesis was to meet growing demand for the development of environmental biomonitors that protect ecosystems and public health. To do this, I determined the potential of oyster shell as a bioindicator of cadmium (Cd) in the environment by determining the mode of Cd uptake and relationships between Cd concentrations in the environment, shell, and soft tissues of juvenile eastern oysters (Crassostrea virginica Gmelin). I performed a review of the literature on the ability of oyster shell to retain metal contaminants and the factors that could affect this process (Chapter 2). I then reared C. virginica …

Kegg_Pull: A Software Package For The Restful Access And Pulling From The Kyoto Encyclopedia Of Gene And Genomes, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

Background: The Kyoto Encyclopedia of Genes and Genomes (KEGG) provides organized genomic, biomolecular, and metabolic information and knowledge that is reasonably current and highly useful for a wide range of analyses and modeling. KEGG follows the principles of data stewardship to be findable, accessible, interoperable, and reusable (FAIR) by providing RESTful access to their database entries via their web-accessible KEGG API. However, the overall FAIRness of KEGG is often limited by the library and software package support available in a given programming language. While R library support for KEGG is fairly strong, Python library support has been lacking. Moreover, there …

Multiscale Molecular Modeling Studies Of The Dynamics And Catalytic Mechanisms Of Iron(Ii)- And Zinc(Ii)-Dependent Metalloenzymes, Sodiq O. Waheed

Dissertations, Master's Theses and Master's Reports

Enzymes are biological systems that aid in specific biochemical reactions. They lower the reaction barrier, thus speeding up the reaction rate. A detailed knowledge of enzymes will not be achievable without computational modeling as it offers insight into atomistic details and catalytic species, which are crucial to designing enzyme-specific inhibitors and impossible to gain experimentally. This dissertation employs advanced multiscale computational approaches to study the dynamics and reaction mechanisms of non-heme Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases, including AlkB, AlkBH2, TET2, and KDM4E, involved in DNA and histone demethylation. It also focuses on Zn(II) dependent matrix metalloproteinase-1 (MMP-1), which helps …

Designing And Synthesizing A Warhead-Fragment Inhibitory Ligand For Ivyp1 Through Fragment-Based Drug Discovery, Samuel Moore

Symposium of Student Scholars

Fragment-based drug discovery (FBDD) is a powerful tool for developing anticancer and antimicrobial agents. Within this, magnetic resonance spectroscopy (NMR) provides a comprehensive qualitative and quantitative approach to screening and validating weak and robust binders with targeted proteins, making NMR among the most attractive strategies in FBDD. Inhibitor of vertebrate lysozyme (Ivyp1) of P. aeruginosa serves as an excellent target because of its active cellular location and implications in clinical prognosis for cystic fibrosis and immunocompromised patients. This study uses current NMR and biophysical techniques to develop a covalent, fragment-linked warhead inhibitor for Ivyp1 through synthetic methods, warhead linking, and …

A Pipeline To Generate Deep Learning Surrogates Of Genome-Scale Metabolic Models, Achilles Rasquinha

School of Computing: Dissertations, Theses, and Student Research

Genome-Scale Metabolic Models (GEMMs) are powerful reconstructions of biological systems that help metabolic engineers understand and predict growth conditions subjected to various environmental factors around the cellular metabolism of an organism in observation, purely in silico. Applications of metabolic engineering range from perturbation analysis and drug-target discovery to predicting growth rates of biotechnologically important metabolites and reaction objectives within dierent single-cell and multi-cellular organism types. GEMMs use mathematical frameworks for quantitative estimations of flux distributions within metabolic networks. The reasons behind why an organism activates, stuns, or fluctuates between alternative pathways for growth and survival, however, remain relatively unknown. GEMMs …

A New Insight Into Fungal Cell Wall Architecture By Functional Genomics And Solid-State Nmr Along With Recent Advancements In Dynamic Nuclear Polarization For Analyzing Biomolecules, Arnab Chakraborty

LSU Master's Theses

This dissertation summarizes the findings related to the way by which supramolecular architecture of fungal cell wall changes with genetic mutation, dispensing genes responsible for biosynthesis of cell wall polysaccharides. This is necessary because without perfect picture of how supramolecular assembly changes with genetic mutation it is hard to assess new anti-fungal targets. Alongside this we have highlighted how recent advancement into Dynamic Nuclear Polarization (DNP) methods improved characterization of biomolecules both in case of labeled and unlabeled samples.

First study utilized Solid-state NMR (SSNMR) which is a non-destructive technique hence enabled us for the first time to deduce how …

Inferring Dynamics Of Biological Systems, Tracey G. Oellerich

Biology and Medicine Through Mathematics Conference

No abstract provided.

Supertertiary Structural Dynamics Modulate Function In Postsynaptic Density Protein 95, George L. Hamilton Iii

All Dissertations

Proteins, RNA, and DNA serve as the primary sub-cellular machinery that give rise to the necessary functions of life. The long-standing paradigm has been that the structures of biomolecules, or the arrangement of the subunits that make up a biomolecule, determine biological function. However, biomolecules are not static objects. Instead, they often undergo structural rearrangements that are crucial to enabling and regulating their functions. In my thesis I present several studies of the interplay between the structures, dynamics, and functions of biomolecules that combine experimental fluorescence spectroscopy and computational methods to probe these systems at the single-molecule level. In particular, …

Design, Synthesis, And Analysis Of Paired Coiled-Coil Peptidic Molecular Building Blocks Used For Linearly Controlled Self-Assembly Of Α-Helical Coiled-Coil Heterodimer Peptide Pairs, Jason Distefano

Chemistry Theses

Molecular building blocks are fundamental to biological synthesis and processes and have been utilized in advanced materials, drugs and drug delivery systems, and biotechnology. Proteins have been used as molecular building blocks for the construction of complex, well-ordered structures. Coiled-coil protein domains are essential subunits used for the oligomerization of protein complexes, gene expression, and structural elements of biological materials. The synthesis and assembly of proteins utilizing coiled-coil motifs are of great scientific interest due to their potential applications in disease treatment, biomechanical motors, nanoscale delivery systems, etc. However, assembling protein complexes with specific morphology is still challenging because …