AUTOMATED-METHOD FOR MODELING 7-HELIX TRANSMEMBRANE RECEPTORS FROM EXPERIMENTAL-DATA

A rule-based automated method is presented for modeling the structures of the seven transmembrane helices of G-protein-coupled receptors. Th e structures are generated by using a simulated annealing Monte Carlo procedure that positions and orients rigid helices to satisfy structur al restraints. The restraints are derived from analysis of experimenta l information from biophysical studies on native and mutant proteins, from analysis of the sequences of related proteins, and from theoretic al considerations of protein structure. Calculations are presented for two systems. The method was validated through calculations using appr opriate experimental information for bacteriorhodopsin, which produced a model structure with a root mean square (rms) deviation of 1.87 Ang strom from the structure determined by electron microscopy. Calculatio ns are also presented using experimental and theoretical information a vailable for bovine rhodopsin to assign the helices to a projection de nsity map and to produce a model of bovine rhodopsin that can be used as a template for modeling other G-protein-coupled receptors.