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Effective Fragment Potentials and the Enzyme Active Site



S E. Worthington, Morris Krauss


Optimization of the binding conformation of a substrate in an enzyme active site using ab initio quantum chemistry methods are intractable since the active site comprises several hundred atoms. However, the active site can be decomposed into an active and spectator region where the spectator residues are represented by effective fragment potentials and reducing the number of all-electron atoms involved in the chemistry to a reasonable level. The effective fragment potentials for electrostatics and polarization are implemented in GAMESS but the repulsive and charge transfer potentials are fit to interaction energies of water with models of the residues. These repulsive/charge transfer potentials are generated for the protein residues and the EFP are then used to optimize binding of a transition state analogue to chorismate mutase (B. subtilis) and small dianions to ribonuclease A. For chorismate mutase the calculated binding conformation compares well to the comarable x-ray structure. The binding of the inhibitor to the glutamate/glutamine mutant active site is then predicted with the optimization including the glutamine residue constrained only at the C α atom. The binding conformations suggest important roles for tyr108 and arg63 which have not been noted earlier. The electrostatic stabilization of the transition state by the active site charge distribution has to be augmented by a specific electronic activation by glu78. In ribonuclease A, the protons are found to move to provide a clustering of the charges to bind the small dianions, phosphate, thiophosphate, and sulfate.
Proceedings Title
Computers & Chemistry
Conference Dates
July 1-6, 1999
Conference Location
Conference Title
5th Conference on Computers in Chemistry / Workshop on New Trends in Computational Methods for Large Molecular Systems


binding conformation, chorismate mutase, effective fragment potentials, enzyme active site, mutant, ribonuclease A


Worthington, S. and Krauss, M. (2000), Effective Fragment Potentials and the Enzyme Active Site, Computers & Chemistry, Szklarska, -1 (Accessed April 23, 2024)
Created May 1, 2000, Updated February 19, 2017