This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
Voltage-gated potassium (KV) currents play a crucial role in shaping and controlling the firing patterns that serve as the fundamental basis for the differential signal processing from the ear to the auditory cortex, with distinct firing patterns observed with high- and low-frequency phenotypes. This is an interesting phenomenon, in the...
Voltage-gated potassium (KV) currents play a crucial role in shaping and controlling the firing patterns that serve as the fundamental basis for the differential signal processing from the ear to the auditory cortex, with distinct firing patterns observed with high- and low-frequency phenotypes. This is an interesting phenomenon, in the...
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in humans and play a role in nearly all physiological processes. Among GPCRs, metabotropic glutamate receptors (mGluRs) are a structurally distinct family of synaptic receptors that are essential in regulating neurotransmission and synaptic plasticity. Due to their important regulatory...
Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. This is an allosteric process and involves conformational coupling between ligand-binding domain and signaling domain of a receptor. This allosteric mechanism of activation is unclear for many receptors. Moreover, for...
Nuclear receptors (NRs) are an important family of transcription factors that often regulate genes in response to ligands and by way of direct interactions with coactivator proteins. Many NR-coactivator pairs have been identified that cooperate to regulate transcription but fully understanding how NRs recruit specific coactivators involves learning which of...
Pattern formation of biological structures involves the arrangement of different types of cells in an ordered spatial configuration. Patterning is thought to involve the spatial organization of molecular pre-patterns that precede and drive subsequent cell differentiation and coinciding morphogenesis. These molecular prepatterns are often, although not exclusively, organized through Turing...
Methanotrophs, bacteria that can metabolize methane, remain a promising solution to mitigating the effects of climate change by removing atmospheric methane and converting it to useful chemical precursors. However, a full understanding of the main enzyme they use to oxidize methane, particulate methane monooxygenase (pMMO), is critical for harnessing their...
DNA double-strand breaks (DSBs) are caused by either endogenous agents or exogenous ionizing radiation and chemicals. Incorrect DSB repair can lead to undesired genome rearrangements. Homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways are two major DNA repair pathways that repair DSBs and maintain genome integrity. When homologous DNA is...
Biological experiments involving the manipulation and analysis of cells have always strived towards greater precision and resolution. Recent advances in micro and nanotechnology have improved the precision of manipulation and the resolution of analysis down to a single cell, thus opening new avenues of investigation. These advances have added a...
Mechanosensation is an essential behavior for cellular health that depends on the interactions between the plasma membrane and stretch-activated ion channels. To date, a few studies have measured the effect of membrane composition on protein behaviors from folding to function. However, the relationship between membrane mechanical properties and these behaviors...
Eukaryotic genomes are organized into chromatin, which acts to regulate access to the organism’s genetic material. A large and diverse class of proteins, known as chromatin modifiers and remodelers, are responsible for regulating the composition and structure of chromatin by monitoring nucleosomes. Chromatin remodelers are involved in multiple cellular processes,...
Cobalt(III) Schiff-base complexes (Co(III)-sb) have been utilized in the literature as antibacterial, antiviral, and inhibitory agents. Recent work has utilized their ability to displace endogenous metals from metalloproteins that exhibit aberrant gain of function pathologies in human disease. Specifically, in this dissertation Co(III)-sb has been applied as inhibitors of pathogenic...
The purpose of my thesis research has been to understand the formation of mitotic chromosome structure by using chromosome micromanipulation. Folding mitotic chromosomes from their loose interphase form into their individualized, compacted form is required for easy handling of the chromosomes for cell division. This process is facilitated by several...
In nearly all Eukaryotes, the membrane-enclosed nucleus contains the vast majority of the cellular genome. Within this sub-cellular compartment, the nuclear architecture facilitates genomic chromatin organization. Controlling chromosomal loci’s spatial positioning relative to subnuclear structures and each other can have local and global effects on gene expression. Moreover, chromatin organization...
Over the last few years, there has been a transition away from traditional engineering materials to new advanced materials that exhibit complex architectures with improved mechanical properties. Most of the inspiration for these new materials comes from nature, where organisms have evolved an immense variety of macro and nanoscale shapes...
Proteins and many other systems are often conceptualized as networks to access analysis methods from the field of network science. Several approaches use molecular dynamics (MD) simulations of proteins to construct networks using correlational statistics. However, in the field of network science, a well-established approach for network construction is solving...
The last decade has witnessed a rapid transformation in our understanding of the structure of chromatin, the nuclear complex of DNA and its structural proteins. While, barring mutations, the DNA sequence in each cell of the human body is the same, it is the structure of the chromatin complex that...
Transcription of nucleic acids (DNA and RNA) is a hallmark of life, taking the information stored within genomic nucleic acids and converting it into a form that is useful for producing the proteins necessary for cellular and organismal function. In eukaryotes, transcription of DNA into messenger RNA (mRNA) requires the...
The three dimensional structure of a protein determines its biological function. How a protein folds, however, has been the central research problem for decades. The intermediates on the folding paths, which the protein can assume transiently, are of particular interest as they not only reveal the structural dynamics of a...
We present two ways in which measures of information can be used for the design and analysis of neural networks in both the brain and the computer. In the brain, stimulus is often represented as a distributed pattern of activity in a network of neurons. The quality of such population...
The hippocampus has been identified as a critical structure for supporting spatial memory processes in both humans and animals alike. Many of these processes such as the ability to self-localize in a given environment as well as engage in goal-directed navigation are thought to depend on the location-specific firing of...
DNA topoisomerases are enzymes present in all domains of life. They are responsible for maintaining the topological state of DNA in cells through supercoiling, relaxation, catenation, decatenation, knotting and unknotting. DNA gyrase is a unique topoisomerase, present mainly in bacteria that can introduce negative supercoils into DNA utilizing ATP hydrolysis....
The structural aspects of biological systems are tightly paired with their functions. This understanding has been demonstrated over a broad range of length scales, spanning the ultrastructure of a cell to the macroscopic architecture of organs. Connecting structure and function relies on the integration of physical and biological sciences to...
Pathogenic bacteria scavenge essential nutrients including metals, amino acids and peptides to survive within the hostile host environment. Bacteria utilize ATP-binding cassette (ABC) transporters, powered by the energy of ATP hydrolysis, to move substrates across cellular membranes. The substrate-binding protein (SBP) shuttles substrate in the periplasm and directs the substrate...
Store-operated Ca2+ entry through Orai1 channels mediate transcriptional, proliferative, and effector cell programs in many cells and are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor, STIM1, to cytoplasmic sites on Orai1. Mutations in Orai1 that block channel activation or evoke constitutive channel activity...
Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated Cas proteins provide an immune-like response in many prokaryotes against extraneous nucleic acids. CRISPR-Cas systems are classified into different classes and types that vary widely in composition, target recognition, and overall mechanism. The main division of CRISPR-Cas systems occurs between...