A modular treatment of molecular traffic through the active site of cholinesterase

We present a model for the molecular traffic of ligands, substrates, and pr oducts through the active site of cholinesterases (ChEs). First, we describ e a common treatment of the diffusion to a buried active site of cationic a nd neutral species. We then explain the specificity of ChEs for cationic li gands and substrates by introducing two additional components to this commo n treatment. The first module is a surface trap for cationic species at the entrance to the active-site gorge that operates through local, short-range electrostatic interactions and is independent of ionic strength. The secon d module is an ionic-strength-dependent steering mechanism generated by lon g-range electrostatic interactions arising from the overall distribution of charges in ChEs. Our calculations show that diffusion of charged ligands r elative to neutral isosteric analogs is enhanced similar to 10-fold by the surface trap, while electrostatic steering contributes only a 1.5- to 2-fol d rate enhancement at physiological salt concentration. We model clearance of cationic products from the active-site gorge as analogous to the escape of a particle from a one-dimensional well in the presence of a linear elect rostatic potential. We evaluate the potential inside the gorge and provide evidence that while contributing to the steering of cationic species toward the active site, it does not appreciably retard their clearance. This opti mal fine-tuning of global and local electrostatic interactions endows ChEs with maximum catalytic efficiency and specificity for a positively charged substrate, while at the same time not hindering clearance of the positively charged products.