Investigating the Structure and Function of IGP Synthase
Amaro, Rommie E.
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https://hdl.handle.net/2142/84180
Description
Title
Investigating the Structure and Function of IGP Synthase
Author(s)
Amaro, Rommie E.
Issue Date
2005
Doctoral Committee Chair(s)
Luthey-Schulten, Zaida A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biophysics, General
Language
eng
Abstract
Using traditional and steered molecular dynamics (SMD) simulations, we induced the conduction of ammonia through the (beta/alpha)8 barrel of hisF. Repeated simulations in combination with Jarzynskis identity were used to determine the free energy landscape for ammonia conduction through hisF and showed, for the first time, that it was indeed energetically feasible for this ubiquitous enzymatic fold to exploit its barrel structure to transport reaction intermediates. The architecture of IGP synthase demonstrates remarkable functionality, and we discovered that four conserved residues at the mouth of the barrel act to exclude water while allowing ammonia to pass. We discovered that a conserved network of interactions, present in all known GATs, may serve as a model of allosteric regulation for the entire enzyme family. Through the use of SMD simulations to induce ligand dissociation and additional experimental kinetic assays, we elicited evidence of the allosteric effect in IGP synthase and found a coupled motion between the unbinding of the cyclase ligand and a hinge-opening motion at the interface, which is disrupted when mutations along the conserved allosteric pathway are made.
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