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Protein-Ligand Interactions: Docking, Design and Conformation Change


Datta, Deepshikha (2003) Protein-Ligand Interactions: Docking, Design and Conformation Change. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/36FS-2262.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:HierDock; protein design; tRNA synthetase
Degree Grantor:California Institute of Technology
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Mayo, Stephen L.
Thesis Committee:
  • Goddard, William A., III (chair)
  • Tirrell, David A.
  • Roberts, Richard W.
  • Mayo, Stephen L.
Defense Date:16 December 2002
Record Number:CaltechETD:etd-03242003-111426
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1086
Deposited By: Imported from ETD-db
Deposited On:27 Mar 2003
Last Modified:11 Feb 2021 00:20

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