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Title:Gas migration inside proteins: Mechanism, characterization, and applications
Author(s):Cohen, Jordi
Doctoral Committee Chair(s):Schulten, Klaus J.
Department / Program:Physics
Subject(s):gas migrations
Abstract:Gas migration inside proteins is a little-studied yet very important topic for many classes of proteins such as globins, oxygenases, and oxidases, which store oxygen gas or use it for enzymatic purposes. One reason why this process has not received prominent attention in recent years was because of difficulties in identifying the pathways taken by oxygen or other gases diffusing inside proteins. The reason for this difficulty is that, unlike typical ligand channels, gas pathways are not visible in a protein's static structure. This thesis rectifies these difficulties, by addressing many of the issues important for finding, understanding, and manipulating gas migration pathways inside proteins. First, it is found and convincingly demonstrated, through the use of a molecular dynamics methodology called locally-enhanced sampling and a novel volumetric oxygen accessibility map method, applied to the hydrogenase enzyme, that gas molecules make their way not through static channels, but through well-defined "pathways", which are completely defined by the details of a protein's thermal motion. This work is then followed up with the development of a new method, called implicit ligand sampling, which allows for the first time to completely identify and energetically characterize every oxygen pathway inside any protein of known structure merely from the protein's equilibrium dynamics. The protein dynamics, in this case, are collected through 10 ns-long molecular dynamics simulations in the absence of internal gas ligands. Implicit ligand sampling is then applied to and validated on the well-studied myoglobin oxygen-storage protein. Finally, if one is to engineer oxygen pathways inside proteins, it is not enough to simply know where such pathways are located, it is also important to understand how these pathways are correlated with protein structure. For this reason, oxygen pathways were computed for a large number of proteins from both the globin and copper-containing amine oxidase protein families. It is found, surprisingly, that the locations of oxygen pathways are not conserevd within protein families, and do not correlate at all with the proteins' tertiary folds. However, a statistically significant correlation was found between the proximity of certain residue types and protein oxygen accessibility.
Issue Date:2007
Genre:Dissertation / Thesis
Other Identifier(s):5635660
Rights Information:©2007 Cohen
Date Available in IDEALS:2012-06-07

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