abstract: Traditionally, allostery is perceived as the response of a catalytic pocket to perturbations induced by binding at another distal site through the interaction network in a protein, usually associated with a conformational change responsible for functional regulation. Here, I utilize dynamics-based metrics, Dynamic Flexibility Index and Dynamic Coupling Index to provide insight into how 3D network of interactions wire communications within a protein and give rise to the long-range dynamic coupling, thus regulating key allosteric interactions. Furthermore, I investigate its role in modulating protein function through mutations in evolution. I use Thioredoxin and β-lactamase enzymes as model systems, and show that nature exploits "hinge-shift'' mechanism, where the loss in rigidity of certain residue positions of a protein is compensated by reduced flexibility of other positions, for functional evolution. I also developed a novel approach based on this principle to computationally engineer new mutants of the promiscuous ancestral β-lactamase (i.e., degrading both penicillin and cephatoxime) to exhibit specificity only towards penicillin with a better catalytic efficiency through population shift in its native ensemble.I investigate how allosteric interactions in a protein can regulate protein interactions in a cell, particularly focusing on E. coli ribosome. I describe how mutations in a ribosome can allosterically change its associating with magnesium ions, which was further shown by my collaborators to distally impact the number of biologically active Adenosine Triphosphate molecules in a cell, thereby, impacting cell growth. This allosteric modulation via magnesium ion concentrations is coined, "ionic allostery''. I also describe, the role played by allosteric interactions to regulate information among proteins using a simplistic toy model of an allosteric enzyme. It shows how allostery can provide a mechanism to efficiently transmit information in a signaling pathway in a cell while up/down regulating an enzyme’s activity.
The results discussed here suggest a deeper embedding of the role of allosteric interactions in a protein’s function at cellular level. Therefore, bridging the molecular impact of allosteric regulation with its role in communication in cellular signaling can provide further mechanistic insights of cellular function and disease development, and allow design of novel drugs regulating cellular functions. / Dissertation/Thesis / Doctoral Dissertation Physics 2020
| Identifer | oai:union.ndltd.org:asu.edu/item:63052 |
| Date | January 2020 |
| Contributors | Modi, Tushar (Author), Ozkan, Sefika (Advisor), Beckstein, Oliver (Committee member), Vaiana, Sara (Committee member), Ros, Robert (Committee member), Arizona State University (Publisher) |
| Source Sets | Arizona State University |
| Language | English |
| Detected Language | English |
| Type | Doctoral Dissertation |
| Format | 235 pages |
| Rights | http://rightsstatements.org/vocab/InC/1.0/ |
Page generated in 0.0017 seconds