This is a proposal for addressing basic questions of acetylcholinesterase(AChE) catalysis and inhibition by small molecules using molecular dynamics simulations by CHARMM. Two immediate tasks are the simulation of the recently proposed gating mechanism with choline and acetate ion in the active site cavity of the solvated protein and dynamics calculations of the interactions in the AChE -soman diastereomers. In order to assess the permeability of the AChE monomer to small ios, an at least 150 ps full simulation should be carried out. Another question is the mobility of the catalytic His and the location of its minimum conformations in native AChE and phosphonylated AChE each compared to trypsin. The dynamics of other components of the active site as compared to that of trypsin will also be studied.
NIH ExPorter
NIH ExPorter