MOLECULAR-DYNAMICS SIMULATION OF H2NSO2C6H4CONH(GLY)(3)OBN BOUND TO THE ACTIVE-SITE OF HUMAN CARBONIC-ANHYDRASE .2.

This paper describes stochastic boundary molecular dynamics simulations of a benzyl-terminated oligoglycine inhibitor, H2NSO2C6H4CO(NHCH2CO)(3)R (SG(3)Bn), bound to the active site of human carbonic anhydrase II (HCAII, EC 4.2.1.1) in the presence of water, The position of the terminal benzyloxy group(R = OCH2C6H5) was not defined in a crystal structure of this complex. The simulation suggested that the benzyl group associated with the hydrophobic residues Phe-20 and Pro-202 and that this association accounted for the decrease in the value of K-d observed for this benzyl-terminated inhibitor relative to other inhibitors with hydrophilic terminal groups. The average conformation observed for the oligoglycines in the inhibitor from the simulation was significantly different from the conformation inferred in the crystal structure. For example, the simulation indicated that the Psi angle of Gly-1 and the Phi angle of Gly-2 shifted by about 50 degrees from their values in the crystal structure with the first 2.5 ps of the 150 ps simulation. The simulation suggested that the calculated average conformation of the oligoglycines in the inhibitor-in its bound state with the protein-was a result ed (1) the formation of hydrogen bonds with the surrounding molecules of water(these were included in the simulation) and (2) an accompanying improvement of pi-face associations with the hydrophobic wall of the protein. These results, and their implications for the design of new inhibitors, are discussed.