Date of Award


Document Type


Degree Name


Organizational Unit

Physics and Astronomy

First Advisor

Kingshuk Ghosh, Ph.D.

Second Advisor

Maria Calbi

Third Advisor

Dinah Loerke

Fourth Advisor

Martin Margittai


Bioinformatics, Molecular dynamics, Protein stability, Thermophile


Organisms that thrive under extreme conditions, such as high salt concentration, low pH, or high temperature, provide an opportunity to investigate the molecular and cellular strategies these organisms have adapted to survive in their harsh environments. Thermophilic proteins, those extracted from organisms that live at high temperature, maintain their structure and function at much higher temperatures compared to their mesophilic counterparts, found in organisms that live near room temperature. Thermophilic and mesophilic homolog protein pairs have identical functionality, and show a high degree of structural and sequential similarity, but differ significantly in their response to high temperature. Addressing the principles of enhanced stability and structural resilience to high temperatures environments is important in furthering our understanding of protein folding and stability, and can be quite useful for protein engineering in industrial and biomedical arenas. Furthermore, understanding temperature dependent protein stability can provide valuable insights into aging and certain diseases.

This work will present the observations from multiple large-scale studies that show meaningful general principles that can be a potential mechanism for thermophilic adaptation. First, from the analysis of the largest data set of thermodynamic data, the roles of reduced thermodynamic parameters upon unfolding, and their association with the unfolded state are discussed. Next, from a first-principle polymer physics model, the contribution from electrostatic interactions are shown to reduce the dimensionality of the unfolded state in thermophilic proteins. Finally, as a result of long time scale molecular dynamics simulations, electrostatic interactions are shown to be the key contributor in the stability of the folded state in thermal stable proteins. The combined results indicate that thermophilic proteins modify their amino acid content to increase the amount of charged side chains to utilize an adaptive strategy of enhancing favorable electrostatic energies. Molecular effects of protein mutations are observed in experimental measurements of protein thermodynamic values and enzymatic activity. However, modified proteins can also be quantitatively linked to cellular health and fitness. The consequences of modified thermodynamic traits seen in thermophilic proteins to the growth rate of several organisms will be discussed.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Lucas Sawle


Received from ProQuest

File Format




File Size

191 p.