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Type of Document	Dissertation
Author	Datta, Deepshikha
URN	etd-03242003-111426
Persistent URL	http://resolver.caltech.edu/CaltechETD:etd-03242003-111426
Title	Protein-ligand interactions: docking, design and protein conformational change
Degree	PhD
Option	Biochemistry and Molecular Biophysics
Advisory Committee	Advisor Name Title William A. Goddard Committee Chair David A. Tirrell Committee Member Richard W. Roberts Committee Member Stephen L. Mayo Committee Member
Keywords	protein design tRNA synthetase HierDock
Date of Defense	2002-12-16
Availability	unrestricted
Abstract Virtual ligand screening has proven to be a successful strategy in drug design. An in house-developed procedure (HierDock), a coarse grain docking method followed by a fine grain search procedure, was used to determine the binding site for sugars in the outer membrane protein A in E.coli, a key interaction in the pathogenesis of neonatal meningitis. These results are being further extended in suggesting possible peptide antagonists and drugs for therapeutic strategies. Prediction of binding site of ligands in proteins, starting with the apo-protein is one of the challenges in the field of virtual ligand screening. HeirDock was modified for accurately predicting the ligand binding sites in apo-proteins that undergoes significant structural changes on binding to a ligand. The method was evaluated for finding the binding site for methionine in methionyl tRNA synthetase. We followed up on our understanding of binding mechanism in aminoacyl tRNA synthetases by attempting to design these enzymes to bind to non-natural amino acids. Using the computational protein design software (ORBIT), a phenylalanyl-tRNA synthetase variant that allows efficient in vivo incorporation of aryl ketone functionality into proteins was designed. Ligand-induced conformation changes are commonly seen in proteins. We have developed a procedure by combining computational protein design with methods from mean-field theory to design protein sequences capable of switching between two completely different protein folds on chelating to metal. This method is potentially useful in characterizing protein sequence-structure relationships.
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