Use of theoretical descriptors to characterize cation-? binding sites in (macro)molecules

A metal cation–π (Na+-tryptophane) interaction was detected in the crystallographic structure of a thermophilic Bacillus stearothermophilus triosephosphate isomerase mutant (bTIMmut). The geometry of this particular interaction between a cation and an aromatic ring was analyzed, and theoretical descriptors were derived. In particular, the program GRID emerges as a rapid diagnostic tool to detect cation–π binding sites in (macro)molecules when an appropriate probe is used. This procedure offers an attractive alternative to ab initio calculated molecular electrostatic potential maps. The influence of different force fields (amber, cvff, cff91) and of a series of parameters [partial charge (q), dielectric constant (e), polarizability (via the Aij term of the nonbond Lennard–Jones potential)] was also tested in optimization procedures. The geometries of the complexes were compared to ab initio (molecular orbital—HF/6-31G**, and density functional theory—DFT[B3LYP]/6-31G**) calculations and experimental geometries of cation–π interactions observed in small molecules crystal structures. This work leads to an optimum methodology that was applied with success to the simulation of the cation–π interaction observed in bTIMmut. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 847–855, 2000