Probing the Active Site of Acetylcholinesterase by Molecular Dynamics of Its Phosphonate Ester Adducts

Molecular dynamics (MD) simulations using CHARMM were performed for the solution structures of the pentacoordinate and tetracoordinate PSCS and PRCS adducts of Torpedo californica (Tc) acetylcholinesterase (AChE) formed with 2-(3,3-dimethylbutyl) methylphosphonofluoridate (soman) to assess the molecular origins of stereoselectivity of phosphonylation. MD simulations were also carried out for the PSCS transients in soman-inhibited trypsin to evaluate the differences in the mode of operation of the two enzymes. Parameters for the pentacoordinate phosphonate fragments were constructed from results of an ab initio calculation at the 6-31G* level for a model compound, and those for the tetracoordinate phosphonate fragments were from MNDO calculations. Starting equilibrium structures for the above and for analogous structures for chymotrypsin were generated and energy-optimized in program YETI. The stereoselectivity of AChE for the levorotatory diastereomers of soman amounts to >5.6 kcal/mol difference in trans...