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Optimizing ligand charges for maximum binding affinity. A solvated interaction energy approach

Domenii publicaţii > Chimie + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Sulea T, Purisima EO

Editorial: J. Phys. Chem. B, 105, p.889-899, 2001.


We show that for a given binding site and a given spatial arrangement of atoms in a ligand, there exists an optimal set of partial charges at the atom centers that will optimize the net electrostatic binding free energy of the ligand. This optimal value can be calculated quite readily from a simple quadratic polynomial with coefficients derivable from a few continuum dielectric solvation calculations using a boundary element (BEM) solution of the Poisson equation. Three examples are presented: (a) the binding of cations to 18-crown-6 ether, (b) the calcium-binding sites of parvalbumin, and (c) ligand binding at the active site of the cysteine protease, cathepsin B. The calculations indicate that potassium is the preferred cation for binding to 18-crown-6 ether and that its charge of 1 eu is close to optimal for binding affinity. Similarly, the optimum charge for a monatomic ligand (with a calcium radius) in the calcium binding sites of parvalbumin is predicted to be about 1.8 eu, in agreement with this site’s preference for divalent cations. These results show how electrostatics provides a mechanism for binding site specificity for a given ionic valency. For cathepsin B, charge preferences around the active site are probed using both monatomic and multiatomic ligands. The notion of charge complementarity should be extended beyond the pairing of oppositely charged groups to also include the selection of the correct charge magnitudes. The concept of optimum ligand charges has profound implications for understanding molecular recognition and for molecular design.

Cuvinte cheie: charge optimization, continuum solvation, binding affinity, optimal charge distribution