Date of Award

4-30-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dr. Donald Hamelberg

Second Advisor

Dr. Suazette Reid Mooring

Third Advisor

Dr. W. David Wilson

Abstract

Proteins have been termed the building blocks of life due to their involvement in practically every biological process that occurs in a living organism. For years now, researchers have sought to uncover the underlying mechanisms employed by biomolecules to carry out such tasks and functions. Initial understanding of proteins and how they function, at the atomic level, was revolutionized by the generation of numerous average static structures via X-ray crystallographic methods. Nevertheless, although one or multiple three-dimensional structures exist for many proteins, biological activity cannot be solely explained by relatively rigid structures. Proteins are dynamic entities governed by their dynamic personalities where biological function is rooted in their internal motions, fluctuations, and conformational changes. However, despite many experimental and computational efforts, how protein motions or dynamics couple protein function remains poorly understood. Here, in this work, we employ standard molecular dynamics (MD) simulations and enhanced sampling methods (Rotatable accelerated MD-dual boost (RaMD-db)) to try and capture a more accurate representation of the dynamic nature of two enzymes, cyclophilin A and choline oxidase. We show that molecular dynamics is a powerful method and is more than capable of acquiring a more accurate representation of the dynamic nature of the enzymes, in comparison to experimental techniques. More so, RaMD-db, because it was able to sample conformational states that were never observed in standard MD. Furthermore, we showed, at an atomic level, how protein motions facilitate and are coupled to biological function in both cyclophilin A (CypA) and choline oxidase. Ultimately, an atomic level description of how protein motions facilitate function, provided by the results in this work, can be utilized for drug design advancement, protein engineering, and to gain a better understanding of protein participation in disease.

Available for download on Sunday, April 26, 2020

Share

COinS