Date of Award

Fall 12-12-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Donald Hamelberg

Abstract

Allostery is a universal process in cellular interaction and function. Allosteric regulation occurs when local changes from a distant site of the biomolecular structure alter the changes at the binding site. Allosteric regulation is an intrinsic property, which is assumed to be a propagation of conformational or dynamical changes through a network of interactions from the regulatory site to the binding site cavity. Despite many approaches, the concept of allostery is vaguely understood, as this phenomenon occurs at different cellular levels for regulation. In this dissertation, we provide more insight on allosteric regulation, using three different protein systems as models to map the theory. Proteins are known as the cellular machineries of living organisms and are involved in most allosterically regulated events. We found that sampling protein dynamics under allostery provided more information on active site activity during function. Furthermore, distal site modifications cause changes both locally and at different parts of the structure, including the active site. Our results demonstrate a link between allosteric regulation and surrounding parameters to produce a structure more suitable for function. The protein structures selected for this work are not only structurally diverse, but also take part in the metabolic pathways of different cellular events to scope the idea of allostery from a wide range of biological systems. We used standard molecular dynamics (MD) to generate conformational ensembles of numerous protein systems and study their allosteric mechanism at the atomic level. Proteins are dynamic in nature, thus, MD simulations coupled with statistical approaches suggest several pathways of interactions between allosteric sites and the active site of the model systems. Our findings could help explain allosteric effects on protein mechanisms, including post-translational modifications and disease-causing mutations of proteins.

DOI

https://doi.org/10.57709/32739416

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