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Computational Study of Bovine β-Lactoglobulin Complexes with Fatty Acids Open Access


Other title
Bovine β-Lactoglobulin
Fluorine bonding
Free energy simulations
Type of item
Degree grantor
University of Alberta
Author or creator
jalili, Nobar
Supervisor and department
Klassen, John (Chemistry)
Examining committee member and department
Hanna, Gabriel (Chemistry)
Klobukowski, Mariusz (Chemistry)
Department of Chemistry

Date accepted
Graduation date
Master of Science
Degree level
This thesis presents studies aimed at delivering a deeper understanding of protein-fatty acids recognition and dissociation processes using molecular dynamics simulations. The focus of this thesis is on theoretical modeling of β-lactoglobulin protein in complex with fatty acid ligands (fluorinated and non-fluorinated). The dynamics of ligand exit from protein binding site is unclear and it is desired to understand whether ligands dissociate from the protein binding site along a well defined dissociation pathway or through a collection of exit pathways. This computational study of β-lactoglobulin and fatty acid complexes was inspired by recent mass spectrometry experiments using blackbody infrared radiative dissociation technique where the dissociation kinetics of these complexes was measured. Potential of mean force calculations and transition state theory were utilized to compute the dissociation rate constant of β-lactoglobulin-fatty acids complexes. Analysis of the calculated free energy profiles provided a more complete picture of the probable intermolecular interactions. The carboxyl group of the fatty acids interacts with variety of the residues on the flexible loops via hydrogen bonds but it is not involved in the interactions with the charged amino acids. There is a late transition state for the dissociation of β-lactoglobulin-fatty acid complexes and most probably the cleavage of the nonpolar interactions of the fatty acid aliphatic chain with protein residues lined in binding cavity is the last step of the activation process. It is not clear how fluorination influences the stability of protein-ligand complexes. Recently, quantitative investigation of the energetics of β-lactoglobulin complex with fluorinated fatty acids proved that fluorocarbon binding within the binding cavity of β-lactoglobulin is stronger than hydrocarbon binding. MD simulations were performed on β-lactoglobulin-fluorinated fatty acids complexes to probe the nature of stabilizing intermolecular interactions in further details. Analysis of the trajectory files revealed fluorine bonding to the polar hydrogen atoms is primarily responsible for the stabilizing effects of fluorination.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Lan Liu, Nobar Jalili, Alyson Baergen, Simon Ng, Justin Bailey, Ratmir Derda and John S. Klassen, J. Am. Soc. Mass Spectrom. 2014, 25, 751-757

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