Physical Sciences and Mathematics Commons^™

Rational Design Of Peptide-Based Materials Informed By Multiscale Molecular Dynamics Simulations, Dhwanit Rahul Dave

Dissertations, Theses, and Capstone Projects

The challenge of establishing a sustainable and circular economy for materials in medicine and technology necessitates bioinspired design. Nature's intricate machinery, forged through evolution, relies on a finite set of biomolecular building blocks with through-bond and through-space interactions. Repurposing these molecular building blocks requires a seamless integration of computational modeling, design, and experimental validation. The tools and concepts developed in this thesis pioneer new directions in peptide-materials design, grounded in fundamental principles of physical chemistry. We present a synergistic approach that integrates experimental designs and computational methods, specifically molecular dynamics simulations, to gain in-depth molecular insights crucial for advancing the …

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 …

Method Development For Enhancing Sensitivity Of Dynamic Nuclear Polarization Nuclear Magnetic Resonance Spectroscopy For Structural Studies Of Pkc-Drug Interactions, Patrick Terrence Judge

Arts & Sciences Electronic Theses and Dissertations

To perform the most relevant structural studies on biological systems, experiments need to be carried out when the target proteins are in their endogenous cellular environment. Nuclear magnetic resonance (NMR) is well-suited to probe the structure and dynamics of a wide variety of systems, including biologically relevant proteins. However, NMR suffers from an inherent lack of sensitivity. Dynamic nuclear polarization (DNP) NMR is a powerful technique that is used to enhance NMR sensitivity by transferring the greater polarization of exogenously doped electron spins to nuclear spins of interest though the use of a high-power microwave source. Solid effect radicals offer …

Molecular Simulation Of Rna Conformational Dynamics : An Example Of Micro-Rna Targeting Messenger Rna : Mir-34a-Msirt1, Parisa Ebrahimi

Legacy Theses & Dissertations (2009 - 2024)

MicroRNA (miRNA), as a distinct class of biological regulators and a ”guide” member of non-coding RNA-protein complexes (RNPs), regulates more than 60% of protein-coding genes expression through base-pairing with targeted messenger RNA (mRNA) in the RNA-Induced Silencing Complex (RISC). Most of miRNAs identified in human, are conserved in other animals, which have preferentially conserved interaction sites particularly in 3’ untranslated regions (3’UTRs) of many human messenger mRNAs.The capability of a single miRNA to target more than hundreds of mRNAs, suggests that miRNAs influence essentially all developmental process and diseases, which also makes them interesting candidates as therapeutics agents. The primary …

Computational Insights On Medicinal Chemistry Targeting Cyp450s, Alexander D. Fenton

Theses and Dissertations--Chemistry

Modern-day medicinal chemistry has provided researchers with a wide variety of tools to not only gather greater insight from their data, but also to generate data in new ways. One such tool is the construction of computational protein models from crystallographic datasets, and their subsequent use to understand the structure-activity relationships of protein-ligand complexes. These models can be utilized for their predictive power to inform the synthesis of, and improvement of, lead compounds. It is the goal of this work to employ such models to the CYP450 enzyme system such that potent and selective inhibitors can be designed, evaluated biologically, …

Advanced Computational Methodologies To Study Binding Free Energies Of Biomolecular Complexes, Rajat Kumar Pal

Dissertations, Theses, and Capstone Projects

Molecular recognition is the basis of biological mechanisms and is a key element to consider while formulating effective and safe drugs. Pharmaceutical drugs are designed so as to bind a target protein even at very low concentrations to alter the diseased conditions without interfering with normal biological processes. In a rational drug design process, this is achieved by acquiring information about the chemical structure and the physical and chemical properties of the target protein receptor to gain insights on how changing the chemical composition of the substrate drug could affect the protein-drug interaction and binding affinities. Computational models are used …

Structural Analysis Of Transient Receptor Potential Vanilloid Type 1 (Trpv1) Channel Protein And Proline Mimics Using Computational Techniques, Kelly A. Raymond

Seton Hall University Dissertations and Theses (ETDs)

Chapter I

The Transient Receptor Potential (TRP) family of ion channels encompasses more than 30 members, which are expressed in many different tissues and cell types.¹ Transient Receptor Potential Vanilloid Type 1 (TRPV1) is part of the TRP family gated by vanilloids, heat and protons.² Molecular modeling will be used in order obtain structural and functional data on TRPV1 in its membrane bound environment. In particular, the transmembrane and C-terminal domain regions of TRPV1 are of particular interest. The S1-S4 region of the channel is the putative ligand-binding segment, while the C-terminal domain is suggested to respond to …

Computational Approaches To Anti-Toxin Therapies And Biomarker Identification, Rebecca Jane Swett

Wayne State University Dissertations

This work describes the fundamental study of two bacterial toxins with computational methods, the rational design of a potent inhibitor using molecular dynamics, as well as the development of two bioinformatic methods for mining genomic data.

Clostridium difficile is an opportunistic bacillus which produces two large glucosylating toxins. These toxins, TcdA and TcdB cause severe intestinal damage. As Clostridium difficile harbors considerable antibiotic resistance, one treatment strategy is to prevent the tissue damage that the toxins cause. The catalytic glucosyltransferase domain of TcdA and TcdB was studied using molecular dynamics in the presence of both a protein-protein binding partner and …