SIMULATION OF ENZYME-SUBSTRATE ENCOUNTER WITH GATED ACTIVE-SITES

We describe a brownian dynamics simulation method that allows investig ation of the effects of receptor flexibility on ligand binding rates. The method is applied to the encounter of substrate, glyceraldehyde 3- phosphate, with triose phosphate isomerase, a diffusion-controlled enz yme with flexible peptide loops at its active sites. The simulations s how that while the electrostatic field surrounding the enzyme steers t he substrate into its active sites, the flexible loops appear to have little influence on the substrate binding rate. The dynamics of the lo ops may therefore have been optimized during evolution to minimize the ir interference with the substrate's access to the active sites. The c alculated and experimental rate constants are in good agreement.