Title: Binding of phenylalanine analogs to phenylalanyl-tRNA synthetase

Speaker: Peter Kekenes-Huskey, California Institute of Technology 

Date/Time: Friday, January 28, 2005, 10:00-11:00 am

Location: Building 980, Room 95 (Sandia NM)

Brief Abstract: A computational strategy has been developed that captures the binding characteristics of phenylalanine analogs in its respective aminoacyl-tRNA synthetase (aaRS). Binding to the aaRS is a requisite for incorporation into a translated protein, therefore this approach can provide an indirect measure of incorporation for a candidate analog. The protocol couples a ligand torsion sampling method, moleculeGL, with a side chain replacement program, SCREAM, to generate conformations that maximize binding. This protocol has been applied to binding of the twenty natural amino acids and several phenylalanine analogs in select hosts and compared to measured kcat/km data. The reported binding energies correlate well with measured kcat/km data for AMP activation, thus establishing the efficacy of the approach. Furthermore, this strategy has been applied to several amino acid analogs of interest, yielding binding data for wild-type proteins, as well as proposed mutations to improve binding.