Computational Chemistry Commons^™

Exploring Ancestral Enzymes Through Sequence Reconstruction And Stability Prediction, Jeyun Park, Masakatsu Watanabe

SACAD: Scholarly Activities

Proteins evolve through sequence changes that shape structure, stability,

and function. Ancestral sequence reconstruction (ASR) infers ancestral

proteins from modern homologs, but many studies focus on sequence

inference without evaluating structural or energetic feasibility.

β-lactamases provide an ideal model due to their evolutionary diversity and

clinical relevance in antibiotic resistance.

Here, we present an integrated ASR workflow combining phylogenetic

inference (IQ-TREE), ancestral reconstruction, and structural and stability

validation using AlphaFold and FoldX. By reanalyzing a curated β-

lactamase dataset and comparing with a recent study (Risso et al., 2013),

we provide a controlled comparison of ancestral sequences, predicted

structures, and …

Quantum Chemical Methods And Multiscale Modeling In Computer-Aided Drug Design, Hunter W. La Force

Chemistry Theses and Dissertations

Computer-Aided Drug Design (CADD) leverages a diverse toolkit of computational methods to accelerate the discovery and development of novel therapeutics. Among these, quantum chemical calculations provide unparalleled accuracy in understanding molecular interactions, albeit at a higher computational cost. This accuracy is crucial for identifying and quantifying fundamental interactions that dictate drug efficacy and selectivity, as exemplified by our investigation of ruthenium polypyridyl complexes. These metal-based compounds are model systems for studying covalent coordination bonds between ruthenium and its ligands and noncovalent interactions with DNA and protein targets. Local Mode Vibrational Theory emerges as a powerful lens within this framework, enabling …

Computational Analysis Of Proton Conductivity Factors In Grotthuss-Style Mechanisms, Brock Dyer

Physics and Astronomy Honors Papers

The mechanism and fundamental molecular properties involved in proton conduction are discussed. Four calculable properties are presented: the proton affinity, binding energy (between protonated and neutral forms), intramolecular tautomerization barrier, and proton hopping barrier. An overview of the computational methods used in this thesis, including an introduction to the many-body Schrödinger equation and Density Functional Theory, as well as a look at Plane-Wave Density Functional Theory and Gaussian-Type Orbital Density Functional Theory are presented. 4,5-dimethyl-[1,2,3]-triazole is used as a model system, with 10 variations being generated with varying amounts and positions of fluorine substitution on the methyl groups. Preliminary calculations …

Computational Study Of Proton Transfer At Transition Metal Hydrides, Megan Ford

Honors Theses

Energy storage in the bonds of common chemical feedstocks is an attractive solution to the unreliability of wind and solar power due to its long term efficiency and easy recoverability. Energy is stored by reducing chemicals like ammonia, formic acid, and hydrogen, the reaction of which is dependent on a catalyst. To catalyze the reaction, the catalyst undergoes a slow proton transfer (PT) step to form what is known as a metal hydride. The sluggish kinetics of this step lower the effectiveness of the catalyst, and therefore must be better understood in order to improve the efficiency of energy storage …

Assessing Fixed-Node Diffusion Monte Carlo For Radical Polymerization Reaction Energetics, Timothy Brian Huber

Graduate Research Theses & Dissertations

The art of quantum chemistry is grounded to the discovery of a time efficient computational method that can capture the essential physics. Historically, the Hartree-Fock method, where an electron moves in the mean field of the other electrons, has provided the orbitals used to construct a single-reference Slater determinant and thus formed the basis for molecular orbital calculations. Kohn-Sham density functionals have become overwhelmingly popular among the chemistry community due to their low computational cost. However, their prediction of thermodynamic properties important in free radical polymerization has shown difficulty due to an artificial delocalization of electron density and spin contamination …

Quantum Computations And Molecular Dynamics Simulations: From The Fundamentals Of Antimicrobial Resistance To Neurological Diseases, Angel Tamez

Electronic Theses and Dissertations

Biophysical phenomena are modeled using a combination of quantum and classical methods to interpret and supplement three distinct and diverse problems in this dissertation. In the first project, decarboxylation reactions are ubiquitous across chemical and biological disciplines, yet the origin of non-catalytic solvent effects remains elusive. Specific solvent structure and energetics have not been well described for the monoanion of malonate, nor corrected from the gas-phase charge-assisted intramolecular hydrogen bond model known as “pseudochair”. In the aqueous phase, a low-lying energy conformer known as the “orthogonal conformation” is computed to be preferred by a three-water cluster of hydrogen bonding over …

Relative Energy Comparison For Various Water Clusters Using Mp2, Df-Mp2, And Ccsd(T):Mp2 Methods, Qihang Wang

Honors Theses

The study of water clusters is an important area of research in many disciplines, such as biology, physical chemistry, and environmental studies. However, due to the difficulty in studying larger water clusters, such as clathrate hydrates, it is beneficial to obtain accurate descriptions of smaller water clusters to use as models for larger systems via computational methods. By starting with small water clusters, such as (H2O)₆, and moving into larger systems it is possible to build up data on various water structures that can determine the energetics of the various geometries within a certain number of water molecules. …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Computational Models To Predict The Inhibition Of Cytochrome P450 3a4 By Selected Natural Compounds, Sushma Thotakura

Theses and Dissertations

Cytochrome P450 3A4 (CYP3A4) plays a pivotal role in the metabolism of xenobiotics. Methylenedioxobenzene containing natural products have been shown to inhibit CYP3A4. Given that these compounds are widely distributed in nature there is a strong potential for drug interaction with many plants used for dietary or medicinal purposes. In this research we have developed two different computational models (Comparative Molecular Field Model and Artificial Neural Network Model) to assist in the identification of potentially strong inhibitors that could be further studied for potential inhibitory effects. These models were used to screen for the CYP3A4 inhibitory effects of 100 naturally …