Molecular Modeling of the Human A1 Adenosine Receptor Angela Bookwalter Oral report #3 March 22, 1999 Advisor: Dr. Jack Wells BME 273 Senior Design Project

Objective The goal of this project is to design and test a three-dimensional molecular model of the seventh transmembrane-spanning region of the human A1 adenosine receptor.

Introduction Adenosine Receptor Purpose of designing model G-protein coupled receptor Reduces oxygen need of working cells Prevents damage in short-term low-level oxygen situations Purpose of designing model Use as structure to design drugs and artificial ligands Suggest information on functioning of receptor in biological situations

Introduction Design tools Insight II version 97.0 molecular modeling software from Molecular Simulations, Inc. Biochemical data from Wells Lab Scientific literature

Design of 3-D Molecular Models Complete Secondary Structure Primary Structure Simple Secondary Structure

Methodology Identification of transmembrane region Hydrophobicity plots for 33 residues Literature research Lipid Membrane

Methodology Initial coordinates Addition of Biochemical Data Selection from similar receptors to mesh with current known locations Addition of Biochemical Data Choosing of Use of Additional Information Available

Methodology Energy and conformation calculations Insight II software Adjustments as dictated by mentors and additional biochemical data Final analysis

Completed Work Acquired basic knowledge of the Insight II software using tutorials Preliminary structure analysis Literature research Development of modeling strategy Preliminary design of secondary structure

Future Work Complete model of secondary structure of protein Adjust model design as new data is acquired Analysis of potential model designs - especially energy minimizations Testing of final model design

Conclusion The goal of this project will be achieved in the next week with a complete design which meets all desired specifications. Therefore, the project is progressing successfully and timely.