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Title page for ETD etd-10152012-130148


Type of Document Dissertation
Author Lemmon, Gordon Howard
URN etd-10152012-130148
Title Development of methods for docking and designing small molecules within the Rosetta code framework
Degree PhD
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
David Tabb Committee Chair
Brian Bachmann Committee Member
Jarrod Smith Committee Member
Richard D'Aquila Committee Member
Keywords
  • macromolecular modeling
  • computational biology
  • strutural biology
Date of Defense 2012-09-18
Availability unrestricted
Abstract
Structure-based drug design is a key challenge for pharmaceutical chemists. By studying the structure of proteins bound to natural substrates, researchers can design small molecules which they predict will bind in a similar fashion. Ligand docking software such as RosettaLigand plays a key role in structure-based drug design by predicting how a small molecule and a protein will interact. In this body of research I present improvements to the RosettaLigand docking algorithm. I first demonstrate a strategy for achieving accurate predictions of HIV-1 protease/protease inhibitor binding affinity. Next I present a tutorial for using a new version of RosettaLigand docking code which I wrote. This new version allows simultaneous docking of multiple ligands, docking with interface design, and uses an XML-script interface. The XML interface allows fully customizable ligand docking protocols. Finally I demonstrate simultaneous docking of waters along with small molecule inhibitors within protein interfaces. Water docking improves Rosetta’s ability to predict the structure of the protein/inhibitor interface.
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