Predicting relative binding free energies of substrates and inhibitors of acetyleholin- and butyrylcholinesterases

The binding of various substrates and inhibitors to acetylcholinesterase an d butyrylcholinesterase has been studied by computational methods. Two laye red ONIOM calculations were completed with the active site, consisting of t he catalytic triad, and all amino acids within a radius of 5 Angstrom from the O-atom in the OH-group of the active amino acid Ser, referring to S200 in AChE and S198 in BChE, together with the different substrates and inhibi tors in the higher layer and the rest of the esterase in the lower layer. T he interaction between substrates or inhibitors and various residues is dis cussed by superimposing the structures of the two esterases. The computer p rogram LUDI is also used for interaction investigations. The charge distrib utions of various atoms of the amino acids in the catalytic triad of the ac tive site were also studied. (C) 2001 Elsevier Science BN. An rights reserv ed.