Computational approach to site-directed ligand discovery.

A computational approach, Systematic Conformational Search & Induced Fit (SCI&FI), to site-directed ligand discovery (Tethering) is presented. SCI&FI has the ability to predict the binding site, binding mode, and bound dynamics of small molecule fragments covalently tethered to a protein. The SCI&FI method was engineered with the ability to model induced fit conformational changes of the protein because of the binding of the tether. SCI&FI generates comprehensive picture of the binding preferences of the tether to the protein by elucidating potential binding sites of the tether and by describing regions of receptor space capable of conformational change because of the binding of the tether. The SCI&FI method provides a complementary approach to experimental tethering. Initial validation of the SCI&FI method is reported by predicting the 3D structure of two Interleukin-2 and an Interleukin-4 tethered-protein systems.