Molecular dynamics simulations of human glutathione transferase P1-1: Analysis of the induced-fit mechanism by GSH binding

We report here a l-ns molecular dynamics simulation on the ligand-free mono mer of human glutathione transferase P1-1 in bulk water. The average confor mation obtained from the last 500 ps of simulation is taken as a model for the ape-structure of this protein and compared to the available crystallogr aphic data. Remarkable changes in the tertiary structure take place during the simulation and are ascribed to the removal of the ligand, They support an induced fit mechanism occurring upon glutathione binding, whose major fe atures can be described in detail. A portion of helix 2 (residues 42-50), w hich participates in the formation of the active site, undergoes the most p rominent conformational changes. Other protein segments, such as the C-term inal loop and helix 4, also show relevant structural rearrangements. All th ese transitions cause a significant shielding from the solvent of the hydro phobic binding site of the co-substrate, whose exposed surface goes from 4. 6 nm(2) in the hole-structure to about 3.1 nm(2) in the ape-conformation. T he results of this simulation are consistent with numerous experimental obs ervations previously obtained on GST P1-1 and provide new insights for thei r explanation at the molecular level. (C) 1999 Wiley-Liss, Inc.